System and method for simulating cellular biochemical pathways

ABSTRACT

The present invention relates to a system and method for examining pathways. In particular, the present invention provides a system and method for examining pathways that underlie cellular functions, specifically signal transduction pathways. One aspect of the invention relates to the prediction of (a) functional properties of a protein, (b) potential interaction partners of the protein, and/or (c) potential target biochemical pathways within which the protein may interact. Thus, according to the invention, the influence of a given stimulus on a biochemical pathway can be assessed.

RELATED APPLICATIONS

[0001] Priority is claimed to U.S. Provisional Application No.60/188,168, filed Mar. 10, 2000, and U.S. Provisional Application No.60/244,694, filed Oct. 31, 2000, both of which are hereby incorporatedby reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to a system and method forexamining pathways. In particular, the present invention provides asystem and method for examining pathways that underlie cellularfunctions, specifically signal transduction pathways.

BACKGROUND OF THE INVENTION

[0003] DNA sequence analysis and recombinant DNA technology are powerfultools in biologic research. With advances in cellular biology, genetics,and computational methods, a deeper understanding of cell function anddisease is emerging. A bulk of current research activity involvesefforts to understand the molecular basis of cellular biochemicalpathways, i.e., the ordered series of biochemical interactions(typically among proteins) that underlie diverse cellular functions.Greater understanding of these processes will foster more rational andeffective design of medicinal therapies.

[0004] The recent completion of initial phases of several genomesequencing projects has provided important new resources forunderstanding cellular biochemical pathways and functions, but moredetail is needed to fully understand many cellular functions. Forinstance, analysis of biochemical pathways, as well as gene and proteinfunctions, are typically performed with complete knowledge of all theplayers known to be involved in the relevant cellular biochemicalpathways. Thus, the ability to simulate cellular biochemical pathwaysand probable interaction partners for a protein under investigationwould be desirable.

SUMMARY OF THE INVENTION

[0005] One aspect of the invention relates to the prediction of (a)functional properties of a protein, (b) potential interaction partnersof the protein, and/or (c) potential target biochemical pathways withinwhich the protein may interact. Thus, according to the invention, theinfluence of a given stimulus on a biochemical pathway can be assessed.

[0006] Another aspect of the invention relates to a system and methodfor simulating cellular biochemical pathways. The invention integratesthe vast information available on cellular biochemical pathways toevaluate and predict the effect of given stimuli on cellular biochemicalpathways. As such, the invention enables investigators working on poorlydefined cellular biochemical pathways to simulate the biochemicalpathway and predict potential protein interaction partners, in order togain further insight into possible cellular biochemical pathways inwhich a target protein may function.

[0007] Another aspect of the invention is a system and method fordemonstrating the signal cascades that occur in certain cells whencertain stimuli are introduced. In an embodiment of the presentinvention, an inference engine linked to a database of known cellularcomponents and reactions generates the signal cascades.

[0008] A further aspect is the incorporation into the system and methodof the present invention of DNA sequence analysis of domains, motifs,and sites in new proteins of interest to enable a User to predict themost likely types of upstream and downstream proteins (or otherbiomolecules) with which a new protein might interact and, subsequently,the potential biochemical pathways within which a new protein might act.This aspect provides new advantages of significantly greater efficiency,confidence, and focus for a User in deciding on potential new avenues ofresearch to pursue. Another aspect of the system and method of thepresent invention is the incorporation of data regarding how the primarysequence of functional sites in biomolecules (eg., proteins) effects thespecificity and efficacy of physical interactions with binding partners.Further, binding constants, rate equations, and reactant concentrationsmay be incorporated into the system and method of the present invention,in order to determine reaction events, pathway activities, and cellfunction outcomes.

[0009] The system and method of the present invention may also be usedfor molecular examination of the relationship between the structure offunctional sites and partner interactions and their relation to theeffects of molecular interventions by genetic variation, pharmaceuticalcompounds or toxic substances on the physical interactions of bindingpartners. Further, the present invention may be used to examine thefunctional consequences of such molecular interventions to biochemicalpathways and cellular events. Examination, with the present invention,of the relationship between sequence variation (molecular genotype)within domains and functional profile within pathways creates newadvantages for the design and selection of appropriate pharmaceuticalcompounds that are unlikely to produce adverse side effects, predictedby the subject genotypic profile.

[0010] In a preferred embodiment, the system and method of the presentinvention simulate signal cascades of cellular biochemical pathways thatoccur when certain stimuli or endpoints are introduced. Instead of usingpre-generated biochemical pathways, the system and method of the presentinvention dynamically generate their results using a simulation modulethat includes an inference engine linked to at least one dynamicdatabase of definitions relating to cellular concepts, components, andreactions.

[0011] In one embodiment of the present invention, a method forsimulating at least one aspect of a cellular biochemical pathway isprovided comprising the steps of: providing information regarding atarget cellular environment and a stimulus event; simulating at leastone aspect of a cellular biochemical pathway based on the stimulus eventand target cellular environment information provided; and textuallyand/or graphically displaying at least one aspect of a cellularbiochemical pathway. A method of the invention can further comprise thesteps of predicting target protein functions and/or predicting potentialtarget protein interaction partners.

[0012] In an embodiment of the present invention, a method forsimulating at least one aspect of a cellular biochemical pathway isprovided comprising the steps of: providing information regarding atarget cellular environment and an endpoint; simulating at least oneaspect of a cellular biochemical pathway based on the endpoint event andthe target cellular environment information provided; and textuallyand/or graphically displaying at least one aspect of a cellularbiochemical pathway.

[0013] In another aspect of the invention, a system for simulating atleast one aspect of a cellular biochemical pathway is provided,comprising: a data input interface; a simulation module; and a displaymodule. Based on cellular environment and input information provided tothe data input interface, the simulation module simulates at least oneaspect of a cellular biochemical pathway by determining the order ofcellular events which occur within the defined cellular environment, andthe display module can display textual and/or graphical representationsof the simulated pathway. Input information may comprise informationregarding cellular context, stimuli, knockouts and/or endpoints. Thesystem of the present invention may optionally comprise a predictionmodule for predicting likely biological outcomes (e.g., apoptosis,lymphocyte activation, etc.), as well as protein interaction partners orgene interaction sites (for transcription factors) based on thesimulated pathway(s).

[0014] In an embodiment of the present invention, the system and methodof the present invention are adapted to be used as an aid in teaching,as educational tools, and/or as a complement to academic textbooks.

[0015] In another embodiment, the system and method of the presentinvention are adapted to be utilized by persons conducting genomic andproteomics research.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1A is a block diagram of a system for simulating cellularbiochemical pathways, in accordance with one embodiment of the presentinvention;

[0017]FIG. 1B is a block diagram of the simulation module of FIG. 1A, inaccordance with one embodiment of the present invention;

[0018]FIGS. 2A and 2B are a flow chart of a preferred control routinefor a forward pathway generation function of the inference engine ofFIG. 1B;

[0019]FIG. 2C is a flow chart of a preferred control routine for areverse pathway generation function of the inference engine of FIG. 1B;and

[0020] FIGS. 3-43 are examples of various graphical displays that can begenerated by the graphical user interface of FIG. 1B.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Cellular pathways involve molecular physical interactions betweenelements in series (typically, though not exclusively, proteins) leadingto an outcome in a cellular process. Thus, a molecular understanding ofthese physical interactions, of pathway interconnections, and of pathwayarchitectures would foster a more rational and effective design ofpharmaceutical therapies when intervention is needed. Unfortunately, theidentity of all the elements and all the interconnections in cellularpathways are not yet established. Gaps exist with respect to many of theelements and their functions. Thus, a major goal of research is toidentify all elements of cellular pathways and to understand themolecular functions and interactions of these elements.

[0022] Central to this effort is the determination of the DNA sequenceof genes that encode these proteins of interest. Examination andcomparison of new DNA sequences with known gene DNA sequences stored inpublic databases routinely provides powerful predictive abilityconcerning the likely function of a new protein. Deeper examination ofsequence data of new proteins can reveal the presence of variousfunctional sites (e.g., domains, motifs, catalytic sites, and sites ofbiochemical modification), which typically constitute regions ofphysical interaction (e.g., protein-protein) between biomolecules. Manyprotein domains, motifs and sites have now been identified and thecharacter of their involvement in diverse molecular interactions areknown.

[0023] As used herein, the term “cellular biochemical pathway” generallyrefers to an ordered series of physical interactions between successivecellular elements leading to an outcome (e.g., signal transduction) in acellular biochemical process. Cellular environment information and inputinformation can be provided to the data input interface in any mannerknown in the art, such as by manual data input through a keyboard orautomated data importation.

[0024] Protein type information can be derived in any manner known inthe art. For instance, a sequence similarity search can be performed,using public or commercial software programs, on a gene or proteinsequence of interest. Typical similarity search platforms include theBLAST family of routines available at www.ncbi.nlm.nih.gov/BLAST. Searchroutines such as BLOCKS, MoST, Pfam, PROSITE, or PROBE that detectconserved protein motifs can then be used if desired. Additionalanalysis of target protein structure, composition, and function can bedone with a variety of web-based platforms.

[0025] As used herein, the term “cellular environment” generally refersto the sum total of all the substances and components within a cellunder consideration. The provided cellular environment information,according to the present invention, represents at least a portion of thetotal cellular environment. Such cellular environment information isgenerally provided as cellular concepts and attributes, which aredefined and described in more detail below. Cellular environmentinformation may comprise, but is not limited to, cell type; protein typeinformation, e.g., cell surface trans-membrane receptor; sub-cellularlocation; identity of motifs; modification sites; and modificationeffects, e.g., activation, inhibition, etc. Input information maycomprise information regarding stimuli, knockouts and endpoints.

[0026] A cellular “concept”, as used herein, is an abstraction ofanything that can be said to exist in space or occur over time withregard to a cellular environment. For instance, all cellular substances,cellular processes, and cellular components are “concepts”. For example,in the statement “adenosine binds to an adenosine receptor in a livercell, which leads to transcription”, the concepts are “adenosine”,“binds to”, “adenosine receptor”, “liver cell”, “leads to” and“transcription”. In grammatical terms, concepts usually represent nounsand verbs.

[0027]FIGS. 1A and 1B are block diagrams of a system 5 for simulatingcellular biochemical pathways, in accordance with one embodiment of thepresent invention. As shown in FIG. 1A, the system 5 comprises aSimulation Module 10, an Output Module 60, a Report Module 70 and aDatabase 80. The Simulation Module 10 is in communication with one ormore Users 20, an Output Module 60, the Report Module 70, and theDatabase 80. The Simulation Module 10 contains all the processing logicfor the system 5.

[0028] The system 5 of the present invention is preferably implementedon a server, which may be or include, for instance, a work stationrunning the Microsoft Windows™ NT™, Windows™ 2000, UNIX, LINUX, XENIX,IBM, AIX, Hewlett-Packard UX™, Novel™, Sun Micro Systems Solaris™,OS/2™, BeOS™, Mach, Apache Open Step™, or other operating system orplatform. However, the system 5 of the present invention could also beimplemented on a programmed general purpose computer, a special purposecomputer, a programmed microprocessor or microcontroller and peripheralintegrated circuit elements, an ASIC or other integrated circuit, ahardwired electronic or logic circuit such as a discrete elementcircuit, a programmable logic device such as a FPGA, PLD, PLA, or PAL,or the like. In general, any device on which a finite state machinecapable of implementing the modules and control routines discussedherein can be used to implement the present invention.

[0029] As shown in FIG. 1B, the Simulation Module 10 preferablycomprises a Graphical User Interface 12 and an Inference Engine 14 and,optionally, an Editor or Compiler 16. In an embodiment of the presentinvention, the Graphical User Interface 12 of the Simulation Module 10may gather input information from a User 20. A User 20 may provideseveral types of input to the Simulation Module 10 using any data inputmethod known in the art. For example, a User 20 may provide pathwaygeneration parameters to the Simulation Module 10. Further, new datarequests may be entered by a User 20 through the Graphical UserInterface 12 to the database 80. A User 20 may also input requests forinformation. Such a request may be entered using a dynamic display. TheSimulation Module 10 may also receive input information from theDatabase 80.

[0030] The Inference Engine 14, working with the Database 80, evaluatesa sequence of logic statements to determine which cellular events shouldbe triggered based on the cellular environment present at the decisionmaking moment.

[0031] As discussed above, the Simulation Module 10 may further comprisean Editor or Compiler 16. The Editor or Compiler 16 may be used by aUser 20 to enter new definitions of attributes, concepts and events, toedit existing definitions and/or compile all changes to the Database 80.In a preferred embodiment, a User 20 may open the Database 80 forviewing. In a further embodiment, the User 20 may edit and/or compileattributes so that the results of the edited attributes may be used bythe Inference Engine 14 of the Simulation Module 10. The User 20 mayalso edit and/or compile concepts so that the results of the editedconcepts may be used by the Inference Engine 14 of the Simulation Module10. Additionally, the User 20 may edit and/or compile events so that theresults of the edited events may be used by the Inference Engine 14 ofthe Simulation Module 10. Optionally, a User 20 may be able to savefiles to the Database 80 using the Editor or Compiler 16 of theSimulation Module 10.

[0032] Several outputs may be generated by the Simulation Module 10. Forexample, requests for data by a User 20 may be sent to the Database 80by the Inference Engine 14 of the Simulation Module 10. The SimulationModule 10 may generate a static graphical display via the Graphical UserInterface 12. The static graphical display may be a display which showsthe pathways created with the input information. For example, the staticgraphical display may be a “step down” or a “mass-action” diagram. Thisstatic graphical display or map may then be exported to the OutputModule 60 and saved as a separate graphics format file. This graphicsfile format may be used as a visual aid by a User 20 conducting apresentation.

[0033] The Simulation Module 10 may also generate a dynamic graphicaldisplay of a “virtual cell” with the pathways that are created with theinput information. This dynamic graphical display may be for forwardpathway generation. The dynamic graphical display may also be a“virtual” three-dimensional cell. A User 20 may utilize the dynamicgraphical display to navigate through the virtual three-dimensionalcell. In this manner, the User 20 may look at different substances inthe virtual three-dimensional cell as reactions occur. The User 20 mayalso zoom in and out of the cell and view the cell from differentvantage points and perspectives. The dynamic graphical display may alsoutilize pictures of cells, cell organelles and other pieces of the cell.These pictures may be, for example, from an image created with anelectron microscope. In this manner, the dynamic graphical displayprovides a User 20 with a realistic presentation of the cell.

[0034] The Simulation Module 10 may additionally generate a written ortextual display of the pathway interactions. Such a display may begenerated in a display window. The Simulation Module 10 may alsocommunicate information to the Output Module 60 to be used to generatefurther types of output or results. In a preferred embodiment of thepresent invention, the Output Module 60 creates a written display of thepathway interactions in a text file. Further, the Simulation Module 10may communicate information to the Report Module 70 to be used togenerate output reports.

[0035] The Database 80 preferably stores signal transductioninformation, which may originate from an operator of the System 5. Theinformation may also originate from the input of a User 20. In a furtherembodiment, the information may originate from an outside database (notshown) which communicates information to the Database 80. The Database80 also preferably stores the definitions of specific attributes,concepts, and events. Alternatively, the definitions of specificattributes, concepts, and events may be stored in a separate dynamicdefinitions database (not shown) that is either a stand-alone databaseor that is an integrated component of the Simulation Module 10. As anadditional alternative, a base definitions database (nor shown) may beincorporated into the Simulation Module 10, and an extended definitionsdatabase (not shown) may be compiled and stored externally from theSimulation Module 10.

[0036] A User 20 may add new attributes to the Database 80. The Database80 may also contain information regarding pathologies. This informationmay comprise signal transduction pathways, as well as different patternsof expression of all the components of the pathways (e.g., protein andDNA level information). For example, a User 20 of the Simulation Module10 makes a query with a protein differentially expressed. In response,information, not only of the possible associated diseases, but also ofthe stage of a certain disease is preferably provided by the SimulationModule 10. Conversely, a search for a pathology or drug will preferablyresult in molecular information about that pathology or drug.

[0037] The Database 80 may also be coded with information specific tochemical areas which focus on signal transduction within plant or animalcellular environments. For example, the Database 80 may be coded withinformation specific to pesticides, herbicides, or fertilizers.

[0038] As discussed above, a concept is an abstraction of anything thatcan be said to exist in space or occur over time with regard to acellular environment. A concept can “inherit” from other concepts, andthey can contain other concepts. For example, a User 20 may create aconcept of a “protein” and assign certain properties to a “protein”concept. If the User 20 wishes to create an instance of a protein (e.g.,“TNF”), the User 20 may define the instance of the protein as a specifictype of “protein” and that instance of the protein can inherit all thespecial properties of a “protein” without having to redefine all theseproperties a second time. In another example, a User 20 may define allthe substances normally contained within mitochondria, and define a“mitochondria” concept that contains all these substance concepts. TheUser 20 may similarly define other cellular structures with theirattending substances and then define a “cell” type to contain all thesestructures. In this manner, both a hierarchy of types and a hierarchy ofstructures may be established.

[0039] A User 20 may add new concepts to the Database 80. These conceptsmay be associated with various attributes. In an embodiment of thepresent invention, these attributes are necessary for efficientprocessing. For example, the attributes may provide informationregarding the shape, color, size or location of a graphic. In a furtherembodiment, the attributes may be informational in nature. For example,the attributes may provide information regarding reference and species.These references may also be tracked by the Simulation Module 10 andexported to the Output Module 60 to facilitate the creation offootnotes, endnotes, articles or reports.

[0040] Concepts of the present invention are capable of being inheritedfrom other concepts (e.g., a breast cancer cell inheriting from ageneric cell). Concepts may also be capable of containing other concepts(e.g., generic cells containing a nucleus, mitochondria, etc.). Conceptsmay additionally be capable of excluding other concepts. Further,concepts may be capable of joining other concepts. In a preferredembodiment of the present invention, user input and editing of conceptfunctions is facilitated through a concept wizard. A concept may also beselected by a User 20 to provide details as to the properties of theconcept. For example, a User 20 may select a protein to provide theprotein sequence with active sites, motifs, signal peptides, etc.

[0041] An event is a formal specification of a chemical reaction orprocess, in terms of (a) the reactants (i.e., what is required for thereaction to occur), (b) the products (i.e., what is produced by thereaction), (c) the inhibitors (i.e., what cannot be present for thereaction to occur), and (d) the context within which the reaction may ormay not occur. In this manner, a process defined as a concept (e.g.,“gene transcription”) is distinguished from one defined as an event, asthe event definition requires the preconditions and post-conditions ofthe process to be defined. For example, in the statement, “adenosinebinds to an adenosine receptor in a liver cell which leads totranscription”, the event is the entire statement, “adenosine” and“adenosine receptor” are the reactants, “gene transcription” is theproduct and “liver cell” is the context.

[0042] A User 20 may add new events to the Database 80 with specificconcepts. Events may be associated with various attributes. Thesevarious attributes may be necessary for efficient processing (e.g.,mobility) or may be informational in nature (e.g., reference andexperimental conditions). Events may be capable of requiring thepresence of certain concepts in the cellular environment before theevent proceeds. Events may also be capable of applying certain conceptsto events (e.g., binds, trimerizes, activates, etc.). Further, eventsmay be capable of producing previously defined concepts. Events mayadditionally be capable of being inhibited by user-defined concepts.Events may also be able to specify within which mediums (e.g., celltypes) the event may occur and may not occur. For example, the eventcould specify that the event occurs when contained in a breast cancercell but not when contained in a liver cell. In a preferred embodimentof the present invention, user input and editing of event functions isfacilitated through an event wizard, as will be explained in more detailbelow.

[0043] An attribute is a property of a concept or event. For example, anattribute of a concept may determine what color the Simulation Module 10should draw the concept if it is represented on a computer screen. Inanother example, an attribute of an event may provide the SimulationModule 10 with information regarding the length of time the eventrequires to proceed. In an embodiment of the present invention, a User20 may add new attributes to the Database 80. The attributes maycomprise a decimal, enumeration (e.g., list), integer or text. Further,an attribute comprising a decimal or integer may further comprise upperand lower bounds. An attribute comprising an enumeration may furthercomprise user entered values.

[0044] The system may be used by one or more Users 20. In one embodimentof the present invention, the system is of a client-server naturecapable of having multiple Users 20 simultaneously. In a furtherembodiment, Users 20 may enter data or input information into theDatabase 80 and allow the Simulation Module 10 to use that data or inputinformation when generating simulations of various pathways.

[0045] In another embodiment of the present invention, a User 20 mustsupply a predefined user identification code and a correspondingpassword in order to access the system. The predefined useridentification code may be used by the system during the interactionwith the database by the User 20. In this embodiment, the User 20 mayonly be provided access to certain predefined areas of the Database 80which correspond to the access level assigned to the User 20. Thepredefined user identification code may also be assigned to a groupidentification code that corresponds to another predefined access level.In addition, to access to certain predefined areas of the Database 80,the user or group identification code may also provide access to asecond database (not shown). In this manner, the User 20 may have accessto at least one database of information with the amount of accesscorresponding to a user or group identification code.

[0046] The Simulation Module 10 may generate a forward cell pathway. Theforward cell pathway may be generated by prompting a User 20 to specify(a) the cell type where the simulation will be conducted and/or (b) thestimulus/stimuli (i.e., initiating event) for the event. The User 20 mayalso exclude certain events from or designate reaction endpoints for theforward cell pathway. These user inputs may be facilitated by an inputinterface. For example, the system may utilize a graphics user interfacefrom which a User 20 may select from highlighted cell types, stimuli,reaction endpoints, or events for exclusion. The Inference Engine 14 ofthe Simulation Module 10 may process events to compare certain conceptsof two or more different concepts to determine if an event shouldproceed.

[0047] As illustrated in FIG. 1A, the Simulation Module 10 utilizesinformation provided by the Database 80 and by Users 20. The InferenceEngine 14 of the Simulation Module 10 then processes the information topredict pathways. In one embodiment of the present invention, theInference Engine 14 may predict a biochemical signal transductionpathway, a small molecule metabolic pathway, a detoxification enzymepathway (e.g., a P450 enzyme-mediated biotransformation to variousmetabolites), toxicology, acute phase reactions, or complement cascades(e.g., classical, alternate, and MBL). In another preferred embodimentof the present invention, the system of the present invention maygenerate diagrams, assist in interpreting the outcome of gene expression(i.e., functional genomics), and/or facilitate drug targetidentification or validation.

[0048] In another preferred embodiment, the system and method of thepresent invention may interface with microarrays to predict changes inthe activity of biochemical pathways in response to diverse conditions.In this embodiment, the activities of biochemical pathways vary inresponse to altered conditions. For example, a common response tovariation in the activity of biochemical pathways is a change in theexpression of many target genes. In another example, variation in theamount of mRNA and the resultant effect on proteins made from the targetgenes contribute to changes in cell function.

[0049] In a further preferred embodiment, microarray chips provide anefficient means to rapidly survey quantitative changes in the expressionof a large set of genes that result in response to changes in theactivity of biochemical pathways. For example, the top proteinstranslated from the mRNAs expressed by the target genes in a given celltype under differing conditions could be rapidly detected on a chip.Further, a change in the amount of protein made by a gene would likelychange the activity of the biochemical pathway in which the proteinproduct functioned. In this manner, the information obtained frommicroarray chips may be imported to the Simulation Module 10 to evaluatehow changes in the expression of large gene sets might change theactivity of diverse biochemical pathways in response to variedconditions. Further, the Simulation Module 10 may be used to examineresponses to many conditions such as response to presentation ofpharmaceutical or toxic substances or the character of cell functionunder pathologic versus normal conditions (e.g., in a B lymphoma cellline verses a normal B cell).

[0050] Transcriptional (microarray) and translational (protein chip)data may be directly uploaded into the Database 80. The Inference Engine14 of the Simulation Module 10 may infer potential signal transductionpathways at the global level and model the pathways. In a furtherembodiment of the present invention, the Simulation Module 10 containssufficient data to not only reconstruct normal cellular pathways butalso pathways associated with disease states. Expression data on geneproducts in biochemical pathways may also be input into the pathwaysgenerated by the Simulation Module 10. The pathways and interactions ofdrugs may be subsequently modeled and additional simulations may begenerated regarding drug action on normal and diseased cells and/ororgans. The Simulation Module 10 may also simulate signal transductionpathways at the cell level to provide output information regarding therole and physiological importance of new gene products or gene productswith altered expression. Further, the present invention may identifyintermediate signal transduction components as potential drug targets.In this embodiment, the list of possible or potential drug targets mayalso be expanded and reprocessed by the Simulation Module 10. In anotherpreferred embodiment, the present invention simulates signaltransduction pathways which are subsequently used to examine thetherapeutic value and possible toxicities of drug candidates.

[0051] The system and method of the present invention may furthercomprise a high throughput screening system (not shown) or otherautomated assay testing device (not shown). This automated assay testingdevice would provide a User 20 with an automated method to performsimulated pathways in a laboratory.

[0052] The system and method of the present invention may alsoincorporate the co-joining of multiple cell types to formmulti-functional tissues, the co-joining of tissues to form organs, andthe co-joining of multiple organs to form organ systems. In this manner,the Inference Engine 14 of the Simulation Module 10 may predict wholebody responses, via signal transduction modeling, to individual andmultiple stimuli.

[0053] The system and method of the present invention may be used as anaid in teaching or educational tools, or as complement to academic textbooks. Academic institutions offering course work in the life sciencescould benefit from using the system and method of the present inventionas a powerful teaching and research tool. Students often comprehenddifficult concepts better when they are presented in an interactive andvisual manner. The system and method of the present invention providesstatic and dynamic pathway displays that can be used by educators toteach students about the complexities of the intracellular environment,including the interrelationships of multiple components and pathways. Inaddition, the present inventions' ability to incorporate new conceptsand events can facilitate learning about the maturation of cells tofully differentiated states, the progression of disease processes likecancer in cells, and the interaction of pharmaceutical products witheach other and cellular components.

[0054] In addition, the system and method of the present invention caneasily be adapted to incorporate the specific concepts and eventsassociated with other types of cellular-based organisms. Thus, forexample, the system and method of the present invention can be used inthe agricultural industry. The U.S. Department of Agricultural hasinitiated several national programs related to plant and animalproduction, product value, and safety through its Agricultural ResearchService (ARS). ARS researchers in many of these national programs couldbenefit from using the system and method of the present invention,because their work also focuses on achieving a better understanding ofintracellular interactions.

[0055] In an embodiment of the present invention, a User 20 may simulateassays using the systems and methods of the present invention. In afurther embodiment of the present invention, the Database 80 andInference Engine 14 may be accessed via an internet website. A User 20may generate forward and reverse pathways through the internet website.Should a User 20 wish to physically run the simulated assays, the User20 may obtain the necessary tools via hyperlinks corresponding tomaterials utilized in the simulation. For example, a User 20 may selecta hyperlink corresponding to a concept or event and information may bepresented regarding purchase information for assay kits or reagents. Ina further embodiment, a User 20 may select a hyperlink corresponding tomaterials utilized in the simulation and the User 20 would be presentedwith a method of directly ordering the materials. For example, a User 20may select a hyperlink corresponding to a concept or event and the User20 may be presented with a transaction window from which the User 20 maypurchase the assay kit or reagent.

[0056]FIG. 2A is a flowchart of a preferred control routine for aforward pathway generation function of the Inference Engine 14 of FIG.1B. The control routine begins at step 18, where the Inference Engine 14accesses the Database 80 to create the cellular environment and pathwaydata structures. For example, the Inference Engine 14 may retrievevalues and indicia corresponding to data implicated by the environmentand pathway.

[0057] Control then continues to step 21, where those substances presentin the cellular context are added to the environment. These substancesmay be determined based upon information stored in the Database 80.Then, at step 22, the substances selected by a User 20 as stimuli areadded to the cellular environment and pathway data structures. Controlthen continues to step 24.

[0058] At step 24, any concepts that a User 20 has specified as“knockouts” are removed from the cellular environment and pathway datastructures. Control then continues to step 26, where all substances inthe cellular environment that are determined to be currently availableto the pathway are marked.

[0059] Next, at step 28, the first reaction defined in the database isdesignated as the current reaction. Control then continues to step 30,where it is determined whether there is a substance present in thecellular environment that would inhibit the current reaction. If thereis, control jumps to step 42, where the reaction is discarded andcontrol continues to step 46. Otherwise, control continues to step 32.

[0060] At step 32, it is determined whether all the reactants of thecurrent reaction are available in the cellular environment. If not allthe reactants are available, control jumps to step 42. Otherwise,control continues to step 34.

[0061] At step 34, it is determined whether any additional user-definedtests of the reaction fail. If so, control jumps to step 42. Otherwise,control continues to step 36, where the Inference Engine 14 adds thereaction to the sequence of events that make up one, or more, of eachcellular pathway.

[0062] Next, at step 38, the Inference Engine 14 adds the products ofthe reaction to the environment and uses the reaction duration to showrelative process time of the products. Control then continues to step46, where the Inference Engine 14 determines if all the reactions havebeen tested. If not, control jumps to step 44. Otherwise, controlcontinues to step 50.

[0063] At step 50, the Inference Engine 14 identifies whether anyendpoints defined by the User 20 have been reached. If so, the controlroutine ends. Otherwise, control continues to step 52.

[0064] At step 52, the Inference Engine 14 determines whether all thesubstances in the cellular environment have been activated. If so, thecontrol routine ends. Otherwise, control jumps to step 26.

[0065] At step 44, the next reaction defined in the Database 80 isdesignated as the current reaction. Control then jumps to step 28.

[0066]FIG. 2B is a flowchart of a preferred control routine for areverse pathway generation function of the Inference Engine 14 of FIG.1B. The method begins at step 54, where the Inference Engine 14 accessesthe Database 80 to add to the environment those substances selected bythe user as endpoints. Control then continues to step 56, where theInference Engine 14 identifies each underived product in the products.

[0067] Next, at step 58, for each underived product identified in step56, the Inference Engine 14 determines whether the product is astimulus. If so, control returns to step 56. Otherwise, controlcontinues to step 62.

[0068] At step 62, all events in the particular cellular environmentwhich may produce the identified stimulus product are added to theproduct's list of producers. Control then continues to step 64, where,for each producer, a new product is generated for each of thecorresponding reactants. Each of the current product's producers issubsequently added to the new product's list of consumers. Control thencontinues to step 66.

[0069] At step 66, it is determined whether there are any remainingunderived products. If so, control jumps back to step 56. Otherwise,control continues to step 68.

[0070] At step 68, a link between each producer and each consumer isestablished for each product. Control then continues to step 69, whereall events are added to the pathway. The control routine then ends.

[0071] In one embodiment of the invention, the definitions are stored inthe Database 80 in a binary format, an editable textual format, or acombination of both. The editable textual format preferably comprises adescriptive computer language called Signal Transduction Language(“STL”), which is one aspect of the present invention. The definitionsmay be generated using STL, and/or compiled into a binary format in anymanner known in the art. In a preferred embodiment of the invention,definitions of attributes, concepts, and events are created, andcellular biochemical pathways are simulated using a set ofgraphics-based forms (ie., instructive, step-by-step screens) generatedby the Simulation Module 10. In an alternate preferred embodiment, a setof graphics-based forms are generated by the Output Module 60.Alternatively, definitions and simulations may be created through adirect, text-based interface using an STL shell.

[0072] As described above, in one embodiment of the present invention,the Graphical User Interface 12 may be implemented with graphics-basedforms. In this embodiment, upon initiating the Simulation Module 10, aUser 20 may be presented with a main menu 100, an example of which isshown in FIG. 3. To perform an action, the User 20 may select one of aplurality of user action buttons 110 a-112 g. Each of the user actionbuttons 110 a-110 g may be associated with one of a plurality ofSimulation Module functions. In the main menu 100 shown in FIG. 3, useraction buttons 110 a-112 g may be associated with the Simulation Modulefunctions Define an Attribute; Define a Substance or Process; Define aReaction; Use STL Editor/Compiler; Generate Pathway; Generate ReversePathway; and Exit Program, respectively.

[0073] Selecting the Define an Attribute button 110 a initiates anAttribute Forms series, which is a series of screens that allows theUser 20 to define a new attribute. Selecting the Define a Substance orProcess button 110 b initiates a Concept Forms series, which is a seriesof screens that allows the User 20 to define a new concept. Selectingthe Define a Reaction button 110 c initiates an Event Forms series,which is a series of screens that allows the User 20 to define a newevent. Selecting the Use STL Editor/Compiler button 110 d initiates anSTL shell, which allows the User 20 to directly edit and compile thetextual definitions. Selecting the Generate Pathway button 110 e orGenerate Reverse Pathway button 110 f initiates a Pathway Forms series,which is a series of screens that allows the User 20 to initiate theInference Engine 14 and simulate at least one aspect of a cellularbiochemical pathway. Finally, selecting the Exit this Program button 110g shuts down the Simulation Module.

[0074] Attribute Forms series

[0075] When a User 20 initiates the Attribute Forms series from the mainmenu 100 by selecting the Define an Attribute button 110 a, an AttributeName screen 200, an example of which is shown in FIG. 4A, may bedisplayed. As shown in FIG. 4A, a User 20 may have the option ofentering an attribute name in field 201 and then selecting the Nextbutton 205 to proceed to the next step in the Attribute Forms series.Alternatively, a User 20 may select the Cancel button 215 to exit theAttribute Forms series. It should be noted that user input in field 201may determine the step that comes “next” in the Attribute Forms series.

[0076] Entering an attribute name in field 201 and clicking the Nextbutton 205 may initiate a Select Attribute Type screen 220, an exampleof which is shown in FIG. 4B. As shown in FIG. 4B, the Select AttributeType screen 220 may allow a User 20 to select one of four types ofattributes: Decimal 221 a; Integer 221 b; Text 221 c; or Enumerated 221d. A User 20 may select one of the attribute types and then select theNext button 225 to proceed to the next step of the Attribute Formsseries. Alternatively, a User 20 may select the Back button 230 toreturn to the previous screen or the Cancel button 235 to exit theAttribute Forms series.

[0077] If a User 20 selects Decimal 221 a or Integer 221 b, followed bythe Next button 225, the Enter Attribute Limits screen 240, an exampleof which is shown in FIG. 4C, may be displayed. As shown in FIG. 4C, aUser 20 may enter numeric attribute values, through the Enter AttributeLimits screen 240, that represent an upper limit 241 b and a lower limit241 a for this attribute. Each of the numeric attribute limits may bemade inclusive by selecting a respective Inclusive indicator 242 a and242 b. A User 20 may select the Next button 245 to proceed to the nextstep of the Attribute Forms series, the Back button 250 to return to theprevious screen, or the Cancel button 255 to exit the Attribute Formsseries.

[0078] Referring back to FIG. 4B, if a User 20 selects Enumerated 221 dfrom the Select Attribute Type screen 220, followed by the Next button225, the Enumerated Enter Attribute Limits screen 260, an example ofwhich is shown in FIG. 4D, may be displayed. As shown in FIG. 4D, a User20 may enter all possible values of an enumerated list. For example, thevalues represented by a “cellular location” type of attribute may beentered by typing the text “membrane bound” into the Value field 261,clicking the Add Value button 262, then repeating the process for anyother values represented by the attribute, e.g., “extracellular”,“nuclear”, etc. Values that have been added may appear in the AllowedValues list 264. From the Enumerated Enter Attribute Limits screen 260,a User 20 may also remove a value from the Allowed Values list 264 byselecting the value from the Allowed Values list 264 and then selectingthe Remove Value button 263. A User 20 may select the Next button 265 toproceed to the next step of the Attribute Forms series, the Back button270 to return to the previous screen, or the Cancel button 275 to exitthe Attribute Forms series.

[0079] Upon selecting the Next button 265 from the Enumerated EnterAttribute Limits screen 260 (FIG. 4D), the Next button 245 from theNumeric Enter Attribute Limits screen 240 (FIG. 4C), or Text 221 c fromthe Select Attribute Type screen 220 (FIG. 4B), the Attribute DefinitionComplete screen 280, an example of which is shown in FIG. 4E, may bedisplayed. As shown in FIG. 4E, the Attribute Definition Complete screen280 may show, in field 281, the STL code that was produced from userselections within the Attribute Forms series. In the example shown inFIG. 4E, “Sample Attribute” was entered as an attribute name in field201 (FIG. 4A), the type selected was Decimal 221 a (FIG. 4B), a value“1” was entered as the lower limit 241 a, and a value of “2” was enteredas the upper limit 241 b (with the inclusive indicators 241 a and 242 bchecked). As shown in FIG. 4E, from the Attribute Definition Completescreen 280, a User 20 may select the Finish button 285 to enter theattribute definition into at least one dynamic database of definitions.A User 20 may optionally select the Back button 290 to return to theprevious screen, or may select the Cancel button 295 to exit theAttribute Forms series.

[0080] Concept Forms Series

[0081] When a User 20 initiates the Concept Forms series from the mainmenu 100 by selecting the Define a Substance or Process button 110 b(FIG. 3), a Concept Name screen 300, an example of which is shown inFIG. 5A, may be displayed. As shown in FIG. 5A, a User 20 has the optionof entering a concept name in field 301, and then selecting the Nextbutton 305 to proceed to the next step of the Concept Forms series.Alternatively, a User 20 may select the Cancel button 315 to exit theConcept Forms series. It should be noted that user input in field 301may determine the subsequent step in the Concept Forms series.

[0082] Entering a concept name in field 301 and clicking the Next button305 may initiate the Select a Base Concept screen 320, an example ofwhich is shown in FIG. 5A. The Select a Base Concept screen 320 mayallow a User 20 to select a base concept from which a newly namedconcept will inherit attributes. This is especially useful in definingreactants and products of reactions. For example, in the reaction “Aphosphorylates B”, the User 20 may define “A” and “B” using “protein” asthe base concept. The concept “phosphorylated B” can then be definedusing “B” as the base concept. A concept does not require a baseconcept. However, a User 20 may select one or more base concepts andthen select the Next button 325 to proceed to the next step of theConcept Forms series. Alternatively, a User 20 may select the Backbutton 330 to return to the previous screen or the Cancel button 335 toexit the Concept Forms series.

[0083] Upon selecting the Next button 325, the Select Any ContainedConcepts screen 340 may be displayed, an example of which is shown inFIG. 5C. The Select Any Contained Concepts screen 340 allows a User 20to select one or more concepts which the concept named in the Select aBase Concept screen 320 (FIG. 5B) is to contain. This feature may beused to create a “cell” or some other general cellular environment. Asdefined and described in more detail below, the concepts that arecontained in a given cellular environment are assumed to be “available”to any biochemical pathway that involves the contained concepts.

[0084] Referring to FIG. 5C, if more than one of a selected containedconcept is present within a given cellular environment, upon selectingthe concept, the number present may be entered in Quantity field 341.For example, a cell which includes a TNFR receptor complex may bedefined as containing three TNFR concepts. A User 20 may select one ormore contained concepts, enter the number of individual conceptscontained in Quantity field 341, and then select the Next button 345 toproceed to the next step of the Concept Forms series. Alternatively, aUser 20 may select the Back button 350 to return to the previous screenor the Cancel button 355 to exit the Concept Forms series.

[0085] Upon selecting the Next button 345 (FIG. 5C), the Select anyExcluded Concepts screen 360 may be displayed, an example of which isshown in FIG. 5D. The Select any Excluded Concepts screen 360 displaysall concepts contained by the base concept, and thus is only utilizedwhen a newly named concept inherits features from existing concepts.This Select any Extended Concept screen 360 is used to exclude specificconcepts from the overall cellular environment. Again, a User 20 mayselect the Next button 365 to proceed to the next step of the ConceptForms series, the Back button 370 to return to the previous screen, orthe Cancel button 375 to exit the Concept Forms series.

[0086] Upon selecting the Next button 365, if the newly named conceptincludes the “substance” attribute (which is true for the “substance”concept or any of its inherited concepts, like “protein”), the CustomizeConcept Appearance screen 380 may be displayed, an example of which isshown in FIG. 5E. The appearance of the concept's graphical presentationmay be customized in the Customize Concept Appearance screen 380. Theshape of the concept graphic may be selected from the Shape Box 382. Therelative size of the concept graphic can be selected in the RelativeSize Box 383, or the up and down buttons 383 a and 383 b may be used toincrease or decrease the relative size incrementally. The color of theconcept graphic may be selected by selecting the Color button 384. ViewBox 381 may show the concept as it will appear, and may be updated afterevery change. A User 20 may select the Next button 385 to proceed to thenext step of the Concept Forms series, the Back button 390 to return tothe previous screen, or the Cancel button 395 to exit the Concept Formsseries.

[0087] When the Color button 384 is selected, a standard Windows® colorpalette screen 384 a may be displayed, an example of which is shown inFIG. 5F. A basic color may be selected from the Basic Colors palette 384b, or a custom color may be defined in the Custom Colors palette 384 cby manipulating parameters of Color Diagram 384 d and selecting the Addbutton 384 e. Once the color is selected, the OK button 384 f may beselected to return to the Customize Concept Appearance screen 380 of theConcept Forms series. Alternatively, the Cancel button 384 g may beselected to return to the Customize Concepts Appearance screen 380without defining a color.

[0088] Upon selecting the Next button 385, the Assign Concept Attributesscreen 3000 may be displayed, an example of which is shown in FIG. 5G.Attributes associated with the newly named concept can be selected fromthe Assign Concept Attributes screen 3000. If the newly named conceptinherits concepts from a base concept, the inherited attributes mayalready be selected. Again, a User 20 may select the Next button 3025 toproceed to the next step of the Concept Forms series, the Back button3050 to return to the previous screen, or the Cancel button 3075 to exitthe Concept Forms series.

[0089] Upon selecting the Next button 3025, the Assign Attribute Valuesscreen 3100 may be displayed, an example of which is shown in FIG. 5H.An attribute value may be defined by selecting an attribute from theAttribute Box 3110, and entering a desired value in the Value Box 3120.For example, selecting “comments” in the Attribute Box 3110 may allowtextual comments to be entered in the Value Box 3120. If the attributeis an enumerated list, a list of allowed values for that attribute maybe displayed in the Value Box 3120 for selection. A User 20 may selectthe Next button 3125 to proceed to the next step of the Concept Formsseries, the Back button 3150 to return to the previous screen, or theCancel button 3175 to exit the Concept Forms series.

[0090] Upon selecting the Next button 3125, the Concept DefinitionComplete screen 3200 may be displayed, an example of which is shown inFIG. 51. The Concept Definition Complete screen 3200 may show the STLcode that may be produced from the User 20 selections. In the exampleshown in FIG. 51, the following selections were made: “Sample Concept”was entered as the name (using the screen shown in FIG. 5A); “protein”was selected as the base concept (using the screen shown in FIG. 5B);“activators”, “comments”, “inhibitors”, “location”, “other databases”and “references” were selected as attributes (using the screen shown inFIG. 5G); values were assigned to “graphiccolor”, “graphicshape”, and“graphicsize” (using the screen shown in FIG. 5E); and the text string“this is a sample concept” was assigned to “comments” (using the screenshown in FIG. 5H). Once the concept definition is complete, the STL codemay be compiled into the definitions database by selecting the Finishbutton 3225. Alternatively, the Back button 3250 may be selected toreturn to the previous screen, or the Cancel button 3275 can be selectedto exit the Concept Forms series without compiling the conceptdefinition into the definitions database.

[0091] Event Forms series

[0092] When a User 20 selects Define a Reaction 110 c from the main menu100 (FIG. 3), the Event Forms series may initiate to display an EnterEvent Description screen 400, an example of which is shown in FIG. 6A.The Event Forms series may be used to define a new chemical reaction orrelationship. As shown in FIG. 6A, a User 20 may have the option ofentering an event description in field 401, and then selecting the Nextbutton 405 to proceed to the next step of the Event Forms series. Theevent description is used for display only and is not parsed ortranslated by the Event Forms series. Alternatively, a User 20 mayselect the Cancel button 415 to exit the Event Forms series. It shouldbe noted that user input in field 401 may determine the next step in theEvent Forms series.

[0093] Upon selecting the Next button 405, the Select Reactants screen420 may be displayed, an example of which is shown in FIG. 6B. One ormore reactants for the event may be selected from the Selection Box 421.According to the present invention, reactants may be any conceptrequired for a cellular reaction or biochemical pathway to proceed. Inthe case of a molecule binding to a receptor, for example, both thestimulus molecule and the receptor molecule are reactants and must beselected. If more than one of a given concept must be present for areaction to proceed, that number may be entered in the Quantity Box 422after the concept is selected from the Selection Box 421. A User 20 mayselect the Next button 425 to proceed to the next step of the EventForms series, the Back button 430 to return to the previous screen, orthe Cancel button 435 to exit the Event Forms series.

[0094] Upon selecting the required reactants in Selected Box 421,optionally entering a reactant quantity in Quantity Box 422, andselecting the Next button 425, the Select Products screen 440 may bedisplayed, an example of which is shown in FIG. 6C. One or more productsfrom the reaction may be selected from the Selection Box 441. Theproducts are concepts produced by the process of the reaction. Accordingto the present invention, processes (e.g., apoptosis and genetranscription) may be products. For example, when the process of thereaction is a molecule binding to a receptor, the product might be abound or activated receptor. If the reaction produces more than oneinstance of a concept, that number can be entered into the Quantity Box442 after the product is selected. A User 20 may select the Next button445 to proceed to the next step of the Event Forms series, the Backbutton 450 to return to the previous screen, or the Cancel button 455 toexit the Event Forms series.

[0095] Selecting the Next button 445 may initiate the Select Inhibitorsscreen 460, an example of which is shown in FIG. 6D. One or moreinhibitors for the reaction may optionally be selected from theSelection Box 461. Inhibitors may be concepts whose presence in thecellular environment means that the reaction cannot proceed. If thereaction is inhibited by more than one instance of a concept, thequantity of concepts may be entered into the Quantity Box 462 after theinhibitor is selected in the Selection Box 461. A User 20 may select theNext button 465 to proceed to the next step of the Event Forms series,the Back button 470 to return to the previous screen, or the Cancelbutton 475 to exit the Event Forms series.

[0096] Upon selecting the Next button 465, the Enter Reaction Structurescreen 480 may be displayed, an example of which is shown in FIG. 6E.The structure of the reaction, i.e., how the reaction components shouldinteract, may optionally be defined from this screen. Reaction structuredefinitions are not required for the simulation of the reaction orcellular biochemical pathways in general, but instead may be utilized,for example, to define how the reactions will be textually and/orgraphically displayed. To define a reaction structure, a process may beselected from the Process Box 481, the concept from which the process isapplied may be selected from the Applied From Box 482, and the conceptto which the process applies may be selected from the Applied To Box483. For example, when the process of the reaction is a molecule “A”binding to a receptor “B”, a User 20 may define the relationship “Abinds to B” by selecting “A” in the Applied From Box 482, “binds to” inthe Process Box 481, and “B” in the Applies To Box 483. The Add button484 a may then be selected to add the reaction structure to theDescriptions List Box 480 a. Alternatively, a reaction structuredefinition may be removed from the Descriptions List Box 480 a byselecting the definition from the Descriptions List Box 480 a andclicking the Remove button 484 b. A User 20 may select the Next button485 to proceed to the next step of the Event Forms series, the Backbutton 490 to return to the previous screen, or the Cancel button 495 toexit the Event Forms series.

[0097] Upon selecting the Next button 485 from the Enter ReactionStructure screen 480 (FIG. 6E), the Enter Event Attributes screen 4000may be displayed, an example of which is shown in FIG. 6F. Certain eventattributes may optionally be assigned from this screen if relevant. Forexample, the event duration (i.e., the amount of time required for theevent to proceed) may be entered in the Event Duration Box 4010.Reactant mobility characteristics and post-reaction presence may also beassigned by selecting the reactant from the Reactants List Box 4020 andchecking Mobility Box 4030 and/or Post-Reaction Presence Box 4040.Preferably, checking the Mobility Box 4030 communicates that thecorresponding reactant will move toward another reactant or reactantswhen the reaction is simulated. Likewise, checking the Post-ReactionPresence Box 4040 communicates that the corresponding reactant will bepresent after the reaction has occurred. A User 20 may select the Nextbutton 4050 to proceed to the next step of the Event Forms series, theBack button 4060 to return to the previous screen, or the Cancel button4070 to exit the Event Forms series.

[0098] Selecting the Next button 4050 from the Enter Event Attributesscreen 4000 (FIG. 6F) may initiate the Enter Event Contexts screen 4100,an example of which is shown in FIG. 6G. Cellular environments may bespecified from the Enter Event Contexts screen 4100. Applicable cellularenvironments may comprise: (1) selecting, in Present Box 4110, celltypes in which the reaction is present; or (2) selecting, in the AbsentBox 4120, cell types in which the reaction is not present. If no celltypes are selected in Present Box 4110 or Absent Box 4120, the reactionwill be applied to all cellular environments. A User 20 may select theNext button 4130 to proceed to the next step of the Event Forms series,the Back button 4140 to return to the previous screen, or the Cancelbutton 4150 to exit the Event Forms series.

[0099] Upon selecting the Next button 4130, the Event DefinitionComplete screen 4200 may be displayed, an example of which is shown inFIG. 6H. Preferably, the Event Definition Complete screen 4200 shows theSTL code that is produced from the user selections throughout the EventForms series. Referring to FIG. 6H, for example, “adenosine binds toadenosine receptor” was entered as the description (using the screenshown in FIG. 6A), “adenosine” and “A2aR” were selected as reactants(using the screen shown in FIG. 6B), and “bound A2aR” was selected asthe product (using the screen shown in FIG. 6C). A reaction descriptionwas entered with process “binds to” being applied from “adenosine” to“A2aR” (using the screen shown in FIG. 6E), “generic cell” was selectedas the event context (using the screen shown in FIG. 6G) and theMobility Box 4030 and Post-Reaction Presence Box 4040 were checked(using the screen shown in FIG. 6F). When a User 20 selects the FinishButton 4210, the STL code is preferably compiled into the definitionsdatabase. The Back button 4220 may be selected to return to the previousscreen or the Cancel button 4230 may be selected to exit the Event Formsseries without compiling the concept definition into the definitionsdatabase.

[0100] STL Editor/Compiler

[0101] When Use STL Editor/Compiler 110 d is selected from the main menu100 (FIG. 3), the STL Editor/Compiler screen 500 may be displayed, anexample of which is shown in FIG. 7. The STL Editor/Compiler screen 500may be used to enter new definitions of attributes, concepts and events,to edit existing definitions, and compile changes to the definitionsdatabase. The STL Editor/Compiler may also be used to open a scriptfile, enter new definitions or edit existing ones, compile the script toplace the changes into the definitions database, and save the scriptchanges. The script files represent an editable, user-readablerepresentation of the definitions contained in the definitions database.

[0102] As shown in FIG. 7, in one embodiment of the invention, the menuoptions available from the STL Editor/Compiler may include File menu510, Edit menu 520, and Tools menu 530. Action options within the Filemenu 510 may include New, Open, Save, Save As, and Exit using standardWindows dialogs or any other mechanism known in the art. Action optionswithin the Edit menu 520 may include Cut, Copy, and Paste functions.Such Edit menu 520 options may be accomplished using any mechanism knownin the art. Action options within the Tools menu 530 include CompileScript and Compile Incrementally functions.

[0103] The Compile Script function may compile the current script intothe definitions database and replaces the previous entries in thedefinitions database. The Compile Incrementally function may compile thecurrent script into the definitions database without replacing theprevious entries in the definitions database. In a preferred embodiment,if script errors are detected, an error message may be displayedspecifying the error that was found, and highlighting the area in thescript where the error occurred. In this embodiment, a User 20 mayrebuild the complete definitions database by executing the CompileScript function to destroy the old database and add in basicdefinitions. Alternatively, a User 20 may execute the CompileIncrementally function to add user-defined definitions. A more detaileddescription of STL is printed below.

[0104] Pathway Forms Series

[0105] The Pathway Forms series may be used to specify the stimulus andcontext of a potential pathway. This process may start the InferenceEngine 14 and generate all possible pathways, applying all knownreactions, until no new intermediate products are produced. The programmay then display three views of the pathway: textual, static anddynamic. When a User 20 initiates the Pathway Forms series from the mainmenu 100 by selecting the Generate pathway button 110 e (FIG. 3), aChoose a Context for the Pathway screen 600 may be displayed, an exampleof which is shown in FIG. 8A. As shown in FIG. 8A, the Next button 605will take you to the next step of the Pathway Forms series, the Backbutton 610 will take you to the previous step, and the Cancel button 615will exit the Pathway Forms series.

[0106] As shown in FIG. 8A, the User 20 may select a cellular contextfor a pathway. This may be a type of cell. Selecting a Next button 605may bring the User 20 to a Choose a Pathway Stimulus screen 700, anexample of which is shown in FIG. 8B. The Choose a Pathway Stimulusscreen 700 may allow the User 20 to choose one or more stimulusconcepts. Stimulus concepts may be concepts that may be introduced tothe cellular context selected in the Choose a Context for the Pathwayscreen 600 shown in FIG. 8A. The User 20 may select concepts from theList Box 701 to serve as stimuli. If more than one instance of a conceptis required to generate a desired result, that number may be entered inthe Quantity Box 702.

[0107] Clicking the Next button 705 may bring the User 20 to the ChoosePathway Intermediate(s) to Knock Out screen 800, an example of which isshown in FIG. 8C. If a User 20 wishes to test how a pathway isinfluenced by the absence of certain concepts, these concepts may beselected from in the List Box 801. The selected concepts will be removedfrom the cellular context. Preferably, however, the selected conceptsare only removed from the immediate corresponding pathway generation.Preferably, the selected concepts are not permanently removed from thepathway generation.

[0108] Clicking the Next button 805 brings the User 20 to the Choose anyPathway Endpoints screen 900, an example of which is shown in FIG. 8D.If the User 20 wishes the pathway to stop when a certain concept hasbeen generated, such pathway endpoints may be selected in Selection Box901. This is useful in determining if a pathway intermediate is producedin complex pathways.

[0109] Clicking the Next button 905 brings the User 20 to the PathwayDefinition Complete screen 1000, an example of which is shown in FIG.8E. The User 20 may click the Finish button 1005 to initiate the displaymodule, which will be explained in more detail below.

[0110] Display Module

[0111] A pathway may be displayed in a textual form, as shown in FIG. 9.FIG. 9 illustrates an example of a Textual Pathway window 1100, whichshows each reaction/event in the order that it was triggered. If thereare more events than will fit on the Textual Pathway window 1100, ascroll bar may appear to the right to scroll the output. The event(s)that is currently being displayed in the dynamic pathway may behighlighted. The Textual Pathway window 1100 may be sized independently,and may be closed without affecting program operation. In a furtherembodiment, the Textual Pathway window 1100 may be ordered by pathwaywith a line between each pathway. In this embodiment, the User 20 has anoption to order the events based upon paths or to order the events basedupon a time stamp assigned to the path. Preferably, the displayedpathway may be highlighted as it occurs.

[0112] The pathway may also be displayed in a static, graphical form, asshown in FIG. 10A. FIG. 10A illustrates an example of a Static Pathwaywindow 1200, which shows a schematic diagram of the concepts involvedand the reactions that occur. If the diagram extends beyond the confinesof the Static Pathway window 1200, scroll bars may appear on the bottomand right. The Static Pathway window 1200 may be sized independently,and may be closed without affecting program operation.

[0113] In one embodiment of the present invention, a pop-up menu ofattributes may appear when the user clicks on a left mouse button on aconcept. From the menu of attributes the User 20 may choose fromattributes such as “references” or “comments”. Choosing an attribute mayactivate a read-only version of the concept editor. The event editor mayalso be activated by clicking on the event arrow corresponding to anevent.

[0114] In one embodiment of the present invention, if the User 20 clicksa left mouse button outside of a concept, a pop-up menu may appearallowing the User 20 to “Cancel” the menu or “Print” the diagram. If theUser 20 chooses to print, a Print window 1300 may appear, an example ofwhich is shown in FIG. 10B. The User 20 may make any changes desired,then click the OK button 1305 to print the diagram.

[0115] The pathway may also be displayed as a dynamic animation, anexample of which is shown in FIG. 11. FIG. 11 illustrates a DynamicPathway window 1400, which shows an animation of the pathway against thebackdrop of a “standard” cell. A shape represents each concept. Thenames of each concept are preferably displayed on the sides, with linespreferably drawn from the names to the concept shapes. The currentelapsed time of the pathway may be displayed on the bottom right. TheDynamic Pathway window 1400 may be sized independently, and may beclosed without affecting program operation.

[0116] If the pathway proceeds towards proliferation, apoptosis,differentiation, or other pre-determined events, the display may displaythe event name on the static display. Gene transcriptions may berepresented by a standard symbol to the left of the nucleus, displayingthe name of the gene or “gene” id, if it is not known.

[0117] As each event is reached in the animation, it may be highlightedin the Textual Pathway window 1100 (FIG. 9).

[0118] In one embodiment of the present invention, if the User 20 clicksthe left mouse button on a concept, a pop-up menu of attributes mayappear (such as “references”, “comments”) that the User 20 can choosefrom. Choosing an attribute may brings up a hyperlink window (FIG. 12).Choosing an attribute may also activate a read-only version of theconcept editor. The event editor may also be activated by clicking onthe event arrow corresponding to an event.

[0119] In one embodiment of the present invention, if the User 20 clicksthe left mouse button outside of a concept, a pop-up menu may appearthat allows the User 20 to “Cancel” the menu, “Run” the animation,“Stop” the animation, “Restart” the animation from the beginning, orchange the “Speed” of the animation. The animation may be stopped andstarted using “Run” and “Stop”, and choosing “Speed” preferably bringsup another menu of speeds from 1 (slowest) to 10 (fastest). The User 20may also choose the views desired from a pathway generator menu. Forexample, the User 20 may choose to display only the static and textualdisplays and those displays may be maximized upon activation of thesystem of the present invention.

[0120] Choosing an attribute may activate a read-only version of theconcept editor. The event editor may also be activated by clicking onthe event arrow corresponding to an event. Any text marked as ahyperlink (e.g., blue and underlined) will preferably bring up a Webbrowser to display information from the Internet when chosen by theuser.

[0121] As illustrated in FIG. 13, Enter User Name and Password window5100 is an example of a user login screen which may be used in thepresent invention. In this embodiment, a User 20 may be required toenter a user login ID and password. The user login ID and password maybe maintained by a client. A User 20 may press the OK button 5102 tocommunicate the entered user login ID and password to the client. Theuser login ID and password may be authenticated against securityinformation stored in a database of the client.

[0122] In an embodiment of the present invention, a preferred staticdisplay of pathways is as shown in window 5110 in FIG. 14. Window 5110may show feedback loops. Feedback loops may be points in pathways inwhich the pathway regulates itself by feeding back to an original pointin the pathway. A User 20 may print the display to a file or directly toa printer. A User 20 may select concepts or events and view all of thedata associated with the selected concept or event.

[0123] In an embodiment of the present invention, a preferred dynamicdisplay of pathways is as shown in window 5120 in FIG. 15.

[0124] In an embodiment of the present invention, a preferred textualdisplay is as shown in window 5140 and window 5130 in FIG. 16 and FIG.17, respectively. As shown in windows 5130 and 5140, the textual displaymay display the user entered initial conditions including user name,pathway type, context, stimulus, exclusions and endpoints. The textualdisplay may be outputted to a file and/or printed. The textual displaymay be organized in several different ways. For example, window 5130shows the textual display ordered by the pathway that occurs in thestatic display. In contrast, window 5140 shows the textual displayordered as they occur in time steps.

[0125]FIG. 18 illustrates a Pathway Generator window 5150 of the presentinvention. The Pathway Generator window 5150 may be the main windowafter the Enter User Name and Password window 5100. The user login IDentered in the Enter User Name and Password window 5100 may be displayedmay be displayed in box 5151 of the Pathway Generator window 5150. Inthe Pathway Generator window 5150, a User 20 may choose from at leasttwo pathway types. For example, a User 20 may select Forward Pathwayradio button 5152 to execute a forward pathway. Alternatively, a User 20may select Reverse Pathway radio button 5153 to execute a reversepathway. A User 20 may select a cell from the Cell Type list box 5154 byhighlighting a cell and selecting the Enable button 5155. This may loadthe cell into the Cell Type window 5156. In an embodiment of the presentinvention, a cell must be chosen and only one cell may be chosen.

[0126] A User 20 may choose a stimulus or stimuli when running theforward pathway generation and may choose a stimulus/stimuli whenrunning the reverse pathway generation. A User 20 may choose a stimulusor stimuli by selecting the Stimuli Search button 5158. Upon selectingthe Stimuli Search button 5158, a User 20 may be presented with theSearch for Stimulus window 5180 shown in FIG. 19. If a User 20 selects astimulus/stimuli, the corresponding information may be displayed in theStimulus window 5157. A User 20 may choose to delete a given stimulus byselecting a stimulus in the Stimulus window 5157 and subsequentlyselecting the Delete button 5159.

[0127] A User 20 may choose a concept knockout when running the forwardpathway generation or reverse pathway generation. A User 20 may chooseto search all available concept knockouts by selecting the KnockoutSearch button 5161. Upon selecting the Knockout Search button 5161, aUser 20 may be presented with the Search for Concepts window 5190 shownin FIG. 20. If a User 20 selects a knockout concept, the correspondinginformation may be displayed in the Concept Knockout window 5160. A User20 may choose to delete a given concept knockout by selecting a conceptknockout in the Concept Knockout window 5160 and subsequently selectingthe Delete button 5162.

[0128] A User 20 may choose a pathway endpoint when running the forwardpathway generation or reverse pathway generation. A User 20 may chooseto search all available pathway endpoints by selecting the EndpointSearch button 5164. Upon selecting the Knockout Search button 5164, aUser 20 may be presented with the Search for Pathway Endpoints window5200 shown in FIG. 21. If a User 20 selects a pathway endpoint, thecorresponding information may be displayed in the Pathway Endpointswindow 5163. A User 20 may choose to delete a given pathway endpoint byselecting a pathway endpoint in the Pathway Endpoints window 5163 andsubsequently selecting the Delete button 5165.

[0129] A User 20 may choose to exclude certain information from thepathway generation by selecting the Event Exclusion Criteria button5166. If a User 20 selects the Event Exclusion Criteria button 5166, anEvent Exclusion Criteria window 5210 may be presented as shown in FIG.22. Any criteria entered by a User 20 in the Event Exclusion Criteriawindow 5210 may be displayed in the Event Exclusion Criteria box 5167. AUser 20 may clear the Event Exclusion Criteria box 5167 by selecting theClear button 5168. A User 20 may execute the pathway based on theselected information by selecting the Run CellTek button 5169. A User 20may clear all information in the Pathway Generator window 5150 byselecting the Clear All button 5170. A User 20 may exit the PathwayGenerator window 5150 by selecting the Exit CellTek button 5171. In apreferred embodiment, a User 20 may save the pathway conditions from agiven pathway to a file. A User 20 may also open information previouslysaved in the Pathway Generator window 5150.

[0130] As shown in FIG. 19, a User 20 may enter a full text search forinformation by entering the full text into the Query String field 5181,selecting the Full String Search check box 5182, and subsequentlyselecting the Search button 5183. A User 20 may also enter partialstring searches by deselecting the Full String Search check box 5182,entering the partial search information into the Query String field5181, and subsequently selecting the Search button 5183. Upon selectionof the Search button 5183, the results of the search are displayed inthe Result box 5184. A User 20 may choose to use the searchedinformation by selecting the given information in the Result box 5184and subsequently selecting the OK button 5185. The selected informationwill then be moved to a corresponding location in the Pathway Generatorwindow 5150. A User 20 may also select the Cancel button 5186 to returnto the Pathway Generator window 5150. When a User 20 is finished usingthe Search for Stimulus window 5180, a User 20 may select the Exitbutton 5187 to return to the Pathway Generator window 5150.

[0131]FIG. 22 illustrates an Event Exclusion Criteria window 5210. AUser 20 may expand the Event Exclusion Criteria window 5210 by selectingthe More button 5211. Expansion of the Event Exclusion Criteria window5210 allows the User 20 to enter more information. A User 20 may selecta pre-defined field to exclude data by selecting from a list in theField list 5212. The pre-defined fields may include references,experiment temperature, assays and species. A User 20 may also choose aselection in the Qualifier list 5213. The Qualifier list 5213 mayinclude equal to, not equal to, less than, greater than, less than orequal to, or greater than or equal to. The options presented in theValues box 5214 may be dependent upon the selection made in the Fieldlist 5212. A User 20 may search for values in the Database 80 using theSearch button 5215. The Operator button 5216 may be a link betweenmultiple rows of event exclusion criteria and may include AND or OR. AUser 20 may enter information by selecting the OK button 5217. Uponselecting the OK button 5217, the Event Exclusion Criteria window 5210may close and entered information may be transferred to the PathwayGenerator window 5150. Alternatively, a User 20 may close the EventExclusion Criteria window 5210 without transferring the information byselecting the Cancel button 5218.

[0132]FIG. 23 illustrates a Concept Editor window 5220. The ConceptEditor window 5220 may be displayed when a User 20 edits conceptinformation or view information from a static display as a read-onlydisplay. A User 20 may search for a reference by selecting a Searchbutton 5221. The Search button 5221 may open a Search for Referencewindow 5260. Upon selection of a reference, the reference informationmay be displayed in an Active Reference box 5222. If a reference isactive (e.g., the refernce is relevant to all entered information), thereference may be indicated with a check mark in the Active check box5223. In an embodiment of the present invention, User 20 must have anactive reference to enter information into the Database 80. A User 20may search for concepts by selecting the Search button 5270. The Searchbutton 5270 may present the Search for Concepts window 5190 (FIG. 20).Alternatively, a User 20 may enter a new concept by selecting a Newbutton 5225. Upon selection of the New button 5225, the New Concept Namewindow 5280 may be presented. A User 20 may delete a concept byselecting a Delete button 5226. A User 20 may indicate if the concept istransportable by enabling the Transportable check box 5256. A User 20may select a class for a given concept by entering the class from a listof classes presented in Class box 5227.

[0133] A User 20 may accept the selected class by selecting the Acceptbutton 5228. A User 20 may also view a detailed listing of all classinformation by selecting a Class button 5229. Upon selection of theClass button 5229, a Class Concepts Hierarchies window 5290 may bepresented. As shown in FIG. 27, the Class Concepts Hierarchies window5290 may show all of the class information. A User 20 may refresh theConcept Editor window 5220 by selecting the Refresh button 5230. A User20 may also Add, Edit, or Delete names by selecting button 5231, 5232,or 5233, respectively, subsequent to selecting a given name in the Nameswindow 5235. Upon selection of a name in the Names window 5235, theselected name may be displayed in the Name Text box 5234 and a drop downlist may be displayed with the name type below the Name Text box 5234.

[0134] A User 20 may cancel the active name by selecting the Cancelbutton 5255. A User 20 may choose to associate a concept with anorganism by selecting the Add/Change button 5236, if an activerelationship exists. Corresponding organism information may be displayedin the Organism window 5238. A User 20 may delete information byselecting the information in the Organism window 5238 and subsequentlyselecting the Delete button 5237. A User 20 may expand the concept fromanother concept by selecting the Add/Change button 5239, if an activerelationship exists. The expanded information may be displayed in theExpands Concept window 5241. A User 20 may delete information byselecting given information in the Expands Concept window 5241 andsubsequently selecting the Delete button 5241. A User 20 may join aconcept with another concept by selecting the Add/Change button 5242, ifan active relationship exists. The joined information may be displayedin the Joins Concept window 5244. A User 20 may delete information byselecting the given information in the Joins Concept window 5244 andsubsequently selecting the Delete button 5243.

[0135] A User 20 may add primitive attributes to a concept by selectingthe Primitive button 5245. Upon selection of the Primitive button 5245,a Primitive Attributes window 5300 may be presented, as shown in FIG.28. A User 20 may choose to search references by selecting theReferences button 5246. Upon selection of the References button 5246, aReferences window 5360 may be presented, as shown in FIG. 34. A User 20may choose to add contains information to a concept (e.g., a container)by selecting the Contains button 5247. Upon selection of the Containsbutton 5247, the Contains window 5310 may be presented, as shown in FIG.29. A User 20 may choose to add database information to a concept byselecting the DB/UI button 5248. Upon selection of the DB/UI button5248, the External Databases window 5370 may be presented, as shown inFIG. 35. A User 20 may choose to add anatomic attributes to a concept byselecting the Anatomic button 5249. Upon selection of the Anatomicbutton 5249, an Anatomic Attributes window 5330 may be presented, asshown in FIG. 31. A User 20 may choose to add scope notes to a conceptby selecting the Scope button 5250. Upon selection of the Scope button5250, a Scope Notes window 5380 may be presented, as shown in FIG. 36. AUser 20 may choose to add molecular attributes to a concept by selectingthe Molecular button 5251. Upon selection of the Molecular button 5251,a Molecular Attributes window 5340 may be presented, as shown in FIG.32. A User 20, may choose to add editorial notes to a concept byselecting the Editorial button 5252. Upon selection of the Editorialbutton 5252, an Editorial Comments window 5390 may be presented, asshown in FIG. 37. A User 20 may choose to add reagents to a concept byselecting the Reagents button 5253. Upon selection of the Reagentsbutton 5253, a Reagents window 5350 may be presented, as shown in FIG.33. A User 20 may choose to associate the active concept with an eventby selecting the Events button 5254. Upon selection of the Events button5254, an Events Editor window 5400 may be presented, as shown in FIG.38.

[0136]FIG. 24 illustrates a Search for Reference window 5260. The Searchfor Reference window 5260 may allow a User 20 to perform partialsearches on reference information. A User 20 may enter authorinformation in the Author text box 5262. A User 20 may enter referencetitles in the Title text box 5263. A User 20 may enter publication yearin the Year text box 5264. A User 20 may enter the distinct referencePMID in the PMID text box 5265. A User 20 may select the Search button5266 to search based on the entered information. All information queriedfrom the Database 80 corresponding to the given criteria may bedisplayed in the Results window 5268. A User 20 may select a referencein the Results window 5268. Upon selection of a reference in the Resultswindow 5268, the full reference information may appear in the FullReference Information window 5269. A User 20 may choose to make areference active by selecting the Make Active button 5267.

[0137]FIG. 25 illustrates a Search for Concept Name window 5270. TheSearch for Concept Name window 5270 may operate in a manner similar tothe Search for Stimulus window 5180 (FIG. 19), the Search for Conceptswindow 5190 (FIG. 20), or the Search for Pathway Endpoints window 5200(FIG. 21).

[0138]FIG. 26 illustrates a New Concept Name window 5280. The NewConcept Name window 5280 may be used to enter a new concept. An activeconcept may be displayed in the Concept window 5281. A User 20 may entera new concept name in the Concept box 5282. A User 20 may search forduplicate names by pressing the Validate button 5283. If a name is not aduplicate, the Validate button 5283 may not be selected by a User 20. Ifa name is a duplicate, an error message may be displayed to the User 20.A User 20 may accept the new name by selecting the Accept button 5284. AUser 20 may exit the New Concept Name window 5280 by selecting the Exitbutton 5285.

[0139]FIG. 27 illustrates a Class Concepts Hierarchies window 5290. TheClass Concepts Hierarchies window 5290 may be used to establish a classrelationship to a concept. A User 20 may view the various class bybrowsing through the hierarchies in the Hierarchies window 5294. A User20 may choose a relation by selecting the Relations button 5291. A User20 may make the relationship active by selecting the Active button 5292.A User 20 may refresh the Hierarchies window 5294 by selecting theRefresh button 5293.

[0140]FIG. 28 illustrates a Primitive Attributes window 5300. ThePrimitive Attributes window 5300 may be used to assign primitiveattributes to a concept. For example, a User 20 may assign values fordisplay to a concept. A User 20 may also indicate whether a concept is astimulus. A User 20 may add the entered primitive attributes to theconcept by selecting the Add button 5301. A User 20 may refresh thePrimitive Display box 5305 by selecting the Refresh button 5303.

[0141]FIG. 29 illustrates a Contains window 5310. The Contains windows5310 may be used for showing containment of concepts in cellular context(e.g., cells, cell structures, etc.). A User 20 may search for conceptsto add to a cellular context. A User 20 may initiate a search byselecting the Search button 5311. Upon selecting the Search button 5311,a User 20 may be presented with a search dialog and/or search results.Concept search results may be selected by a User 20 for containment inthe cellular context. Such selected concepts may be displayed in theContains Concept box 5316. Similarly, a User 20 may select concepts toexclude from the cellular context. Such concepts may be displayed in theExcludes Concepts box 5319. A User 20 may also locate concepts tocontain in or exclude from the cellular contexts by utilizing a batchquery as discussed in reference to FIG. 30.

[0142]FIG. 30 illustrates a Query window 5320. A User 20 may utilize theQuery window 5320-to execute a batch import of concepts in the ContainsConcept box 5316 or the Excludes Concepts box 5319. A User 20 may chooseto include or exclude an organism by selecting Include button 5321 orExclude button 5322, respectively. A User 20 may choose to include orexclude an anatomic by selecting Include button 5323 or Exclude button5324, respectively. After selecting the appropriate include or excluderadio button, a User 20 may choose organism specific information byselecting the Query button 5325, selecting the desired concepts, andselecting the Add button 5326. Similarly, a User 20 may choose anatomicinformation by setting up a search by selecting the desired contextuallimitations (e.g., developmental stage, organ, tissue, cell type, etc.)and search term connectors (e.g., AND, OR, etc.). A User 20 may executethe search by selecting the Query button 5327. A User 20 may selectclass information by selecting the Query button 5328 to find concepts,selecting the desired concepts and then selecting the Add button 5329.If a User 20 wishes a class to be displayed with all sub-classes orinherited classes, a User 20 may select the Expand check box 5321 a. AUser 20 may execute individual queries for an organism, anatomic orclass by selecting the corresponding query button. A User 20 user mayexecute a combination query for an organism, anatomic and/or class byselecting the Combination Query button 5321 b. The Display box 5321 cmay display all information resulting from any searches or queries. AUser 20 may send information displayed in the Display box 5321 c to theContains Concept box 5316 or the Excludes Concepts box 5319 by selectingthe information and selecting the To Contains button 5321 e. A User 20may search for general concepts by selecting the Search button 5321 d.

[0143]FIG. 31 illustrates an Anatomic Attributes window 5330. A User 20may use the Anatomic Attributes window 5330 to associate anatomicinformation (e.g., organ, tissue, cell line, etc.) with a concept. TheTop Display window 5331 displays information regarding an activereference. An active reference is a reference associated with a givenconcept. When new information is added to a concept, a new reference maybe added. New reference information may be displayed in an Active IDReference box 5333. Line item information for a new reference may bedisplayed in the Line Item Display box 5332. The Add/Change buttons5334, 5336, 5338 and 5335 may be used to add and/or change informationregarding developmental stage, organ, tissue and/or cell type. When aUser 20 selects the Accept button 5339, information entered through theAnatomic Attributes window 5330 is validated and entered into theDatabase 80.

[0144]FIG. 32 illustrates a Molecular Attributes window 5340. A User 20may use the Molecular Attributes window 5340 to associate molecularinformation with a concept. The Top Display window 5341 may displayinformation regarding an active reference. The Member of Gene/ProteinFamily window 5342 displays information regarding membership of areference or concept in a gene or protein family. The Has a PrototypeHomolog window 5343 displays information regarding prototype homologs areference or concept may have. A User 20 may select Domains radio button5344, Motifs radio button 5345, Post-Translational Modifications radiobutton 5346, Activated By radio button 5347 or Inhibited By radio button5348 to display corresponding Active ID information in Active ID Displaybox 5349. The References box 5349 e may display more detailed referenceinformation regarding the Active ID information corresponding to selectDomains radio button 5344, Motifs radio button 5345, Post-TranslationalModifications radio button 5346, Activated By radio button 5347 orInhibited By radio button 5348.

[0145]FIG. 33 illustrates a Reagents window 5350. Top Display window5351 may display information regarding an active reference. When a User20 selects the Add button 5355, the User 20 may be prompted to enter areagent name. Upon entering a reagent name, the reagent name may bedisplayed in Middle Display window 5352. A User 20 may add referencesassociated with each reagent in Bottom Display window 5353 by selectinga given reference displayed in Bottom Display window 5353 andsubsequently selecting the Add button 5355.

[0146]FIG. 34 illustrates a References window 5360. The Referenceswindow 5360 may display references associated with a given concept. AUser 20 may choose to activate a reference by selecting a reference froma list of references and subsequently selecting an Add Active button5364. In the embodiment illustrated in FIG. 34, a User 20 may select aTo ‘Search’ button 5363 to jump to the Search for Reference window 260(FIG. 24).

[0147]FIG. 35 illustrates an External Databases window 5370. A User 20may utilize the External Databases window 5370 to identify externaldatabases for use by the Inference Engine 14. These external databasesmay be utilized by the Inference Engine 14 in conjunction with theDatabase 80. A User 20 may also utilize the External Databases window5370 to identify unique identifiers associated with a concept.

[0148]FIG. 36 illustrates a Scope Notes window 5380. A User 20 mayassociate scope notes with a concept by entering the scope notes andselecting the Add button 5386. When a User 20 enters scope notes,selects the Add button 5386 and selects the Exit button 5382, theentered scope notes may be displayed in the Upper Display window 5387.Line item information may be displayed in Lower Display window 5381. AUser 20 may select a line item in Lower Display window 5381.Subsequently, a User 20 may select an Edit button 5385 to edit theselected line item. A User 20 may also select a Delete button 5384 todelete the selected line item.

[0149]FIG. 37 illustrates an Editorial Comments window 5390. A User 20may associate editorial comments with a concept by entering theeditorial comments and selecting the Add button 5396. When a User 20enters editorial comments, selects the Add button 5396 and selects theExit button 5392, the entered editorial comments may be displayed in theUpper Display window 5397. Line item information may be displayed inLower Display window 5391. A User 20 may select a line item in LowerDisplay window 5391. Subsequently, a User 20 may select an Edit button5395 to edit the selected line item. A User 20 may also select a Deletebutton 5394 to delete the selected line item.

[0150]FIG. 38 illustrates an Event Editor window 5400. A User 20 mayutilize the Event Editor window 5400 to enter information associatedwith events. Active Reference window 5401 may display an activereference. Event window 5402 may display the list of events associatedwith the active reference. A User 20 may add an event by selecting theNew Event button 5400 a. A User 20 may search for an event by selectingSearch Event button 5408. Upon selection of the Search Event button5408, the Search for Event Name window 5405 may be presented. Nameswindow 5403 may display names and types of events. A User 20 may add oredit the names in Names window 5403 by entering information into Textwindow 5404. In an embodiment of the present invention, a User 20 mustenter relevant information into the Requires window 5405 and theProduces window 5406. A User 20 may associate an event with acontroversy flag by selecting the Controversy Flag check box 5407. AUser 20 may select concepts by which the event is inhibited by selectingthe Add button 5400 b. A User 20 may also select where an event occursby adding location information to a Cellular Location window 5400 c. AUser 20 may select a variety of different attributes to be associatedwith the event by selecting Constants button 5400 d, Attributes button5400 e, References button 5400 f, Editorial button 5400 g, Experimentalbutton 5400 h, Containers button 5400 i, DB/UI button 5400 j, or Scopebutton 5400 k.

[0151] Upon selecting Constants button 5400 d, a User 20 may bepresented with Biochemical Constants window 5410 (FIG. 40). Uponselecting Attributes button 5400 e, a User 20 may be presented withEvent Attributes window 5420 (FIG. 41). Upon selecting Experimentalbutton 5400 h, a User 20 may be presented with Experimental Conditionswindow 5430 (FIG. 42). Upon selecting References button 5400 f, a User20 may be presented with References window 5360 (FIG. 34). Uponselecting Editorial button 5400 g, a User 20 may be presented withEditorial Comments window 5390 (FIG. 37). Upon selecting DB/UI button5400 j, a User 20 may be presented with External Databases window 5370(FIG. 35). Upon selecting Scope button 5400 k, a User 20 may bepresented with Scope Notes window 5380 (FIG. 36). Upon selecting SearchConcepts button 5400 l, a User 20 may be presented with Search forConcept Name window 270 (FIG. 25).

[0152]FIG. 39 illustrates a Search for Event Name window 5405. TheSearch for Concept Name window 5405 may operate and be utilized in amanner similar to the Search for Stimulus window 5180 (FIG. 19), theSearch for Concepts window 5190 (FIG. 20), or the Search for PathwayEndpoints window 5200 (FIG. 21).

[0153]FIG. 40 illustrates a Biochemical Constants window 5410. ActiveReference window 5411 may display an active reference. A User 20 mayenter a maximum velocity in Vmax window 5412. A User 20 may enter aMichaelis constant in Km window 5413. A User 20 may enter an equilibriumconstant in Keq window 5414. A User 20 may enter a dissociation constantin Kd window 5415. A User 20 may indicate that all constants are knownby selecting Completed Constants check box 5416. Kinetic Display checkbox 5417 may be selected to indicate that the forward and reversekinetic constants are known. A User 20 may enter a reverse kineticconstant in Reverse Rate window 5418. A User 20 may enter a forwardkinetic constant in Forward Rate window 5419. Upon selection of Acceptbutton 5410 a, information entered in Biochemical Constants window 5410may be validated and entered in Database 80.

[0154]FIG. 41 illustrates an Event Attribute window 5420. An event namemay be displayed in Event Name window 5421. A User 20 may add attributesto the event in the Has Attributes window 5422. A User 20 may add testattribute conditions to the event by selecting Add button 5420 a. A User20 may add information that modifies an attribute of an event byselecting the Add button 5420 b. A User 20 may add information thatapplies to an event by selecting the Add button 5420 c associated withthe Applies Process window 5420 d.

[0155]FIG. 42 illustrates an Experimental Conditions window 5430. ActiveReference window 5431 may display an active reference. Line items forall of the experimental condition information and associated referenceIDs may be displayed in Experimental Conditions Display window 5432.When a User 20 selects a line item in Experimental Conditions Displaywindow 5432, appropriate reference information may be displayed inReference window 5433. When a User 20 searches for an assay usingAdd/Change button 5430 b, a corresponding assay name may be displayed inAssay Name window 5434. When a User 20 searches for a preparation typeusing Add/Change button 5430 c, a corresponding event preparation typemay be displayed in Sample Preparation Type window 5435. AssayDescription window 5436 may display an assay description. Assay Bufferwindow 5437 may display assay buffer information. Temperature window5438 may display the experimental temperature. The information enteredinto the Experimental Conditions window 5430 may be verified and enteredinto the Database 80 by selecting the Accept button 5430 a.

[0156]FIG. 43 illustrates an Excluded window 5440. The Excluded window5440 may be displayed upon selection of the Containers button 5400 i(FIG. 38). A User 20 may utilize the Excluded window 5440 to selectcontainers from which the event is excluded. A User 20 may search for agiven container upon selecting Search button 5440 a. A User 20 may add agiven container by selecting the Add button 5440 b.

[0157] STL Shell

[0158] Examples are now presented for demonstration of grammar andrepresentation only. Statements may have no basis in scientific fact.

[0159] Attributes:

[0160] Attributes are used to annotate concepts and events. They areplaceholders that represent information that can be assigned to aconcept or an event. The mass of an object, the color of a protein onthe screen, and all of the parameters that define how an object willmove are all described by attributes.

[0161] The formal specification for defining an attribute is as follows:

[0162] ATTRIBUTE <attribute name> IS [ANY] [INTEGER|REAL|TEXT|OF][<value list>] [FROM [EXACTLY] <number> TO [EXACTLY] <number>][INCLUSIVE].

[0163] The grammar in square brackets [ ] is optional.

[0164] Some specific examples of definitions (with explanations):

[0165] Attribute “mass” is any real.

[0166] This statement defines an attribute called “mass” that can equalany real (decimal) number.

[0167] Attribute “abstract” is any text.

[0168] This statement defines an attribute called “abstract” that canequal any text.

[0169] Attribute “location” is any of “membrane-bound”, “extracellular”,“cytoplasmic”.

[0170] This statement defines an attribute called “location” that canhave any one of the values “membrane-bound”, “extracellular” or“cytoplasmic”.

[0171] Attribute “color” is any integer from 1 to 10 inclusive.

[0172] This statement defines an attribute called “color” that can haveany integral value greater then or equal to 1, and less than or equal to10. The “inclusive” keyword means that both the from-value and theto-value can be equal to their limits—a shorthand way of stating fromexactly 1 to exactly 10.

[0173] Attribute “weight” is any real from 0.3.

[0174] This statement defines an attribute called “weight” that can haveany real value greater than 0.3.

[0175] Attribute “height” is any real to exactly 14.3.

[0176] This statement defines an attribute called “height” that can haveany real value less than or equal to 14.3.

[0177] Some of the attributes will be used by the Simulation Module 10to determine whether or not a reaction will proceed. Most attributeswill be used by the dynamic graphic display of the Simulation Module 10to determine how the events will be represented on the screen.Attributes can also be used to store information about the concepts forhyperlinks and other data displays.

[0178] The following is a list of attributes that may be directly usedby the system and method of the present invention.

[0179] Attribute Name, Purpose

[0180] Substance: Any concept that has this attribute will be listed asa substance in certain lists in the Concept, Event and Pathway wizards.Does not require any particular value to be assigned.

[0181] Process: Any concept that has this attribute will be listed as aprocess in the Process list in the Event wizard. Does not require anyparticular value to be assigned.

[0182] Structure: Any concept that has this attribute will be listed asa “structure” (cell or cellular component) in certain lists in theConcept, Event and Pathway wizards. Does not require any particularvalue to be assigned.

[0183] Duration: Assigned to an event, determines the length of time inseconds the event requires to proceed. May be a decimal number.

[0184] Graphicshape: Assigned to a concept, determines the shape of theconcept in graphical presentation. Enumerated list with the followingelements: none, triangle, square, circle.

[0185] Graphicsize: Assigned to a concept, determines the relative sizeof the concept in graphical presentation. Number from 1 to 100.

[0186] Graphiccolor: Assigned to a concept, determines the color of theconcept in graphical presentation. Long integer in RGB format.

[0187] Location: Assigned to a concept, determines the starting cellularlocation of the concept in the dynamic graphical presentation.Enumerated list with the following elements: MB (membrane bound), Cyt(cytoplasmic), Comp (complexed), Nuc (nuclear), EC (extracellular) andER (endoplasmic recticulum).

[0188] Mobile: Assigned to an event, determines which reactant(s) in theevent will move in the dynamic graphical presentation. Consists of astring of ‘Y’ or ‘N’ characters, ‘Y’ means will move and ‘N’ means won'tmove. The characters are given in the order that the reactants arelisted.

[0189] Postevent: Assigned to an event, determines which reactant(s) inthe event will remain visible after the event is over in the dynamicgraphical presentation. Consists of a string of ‘Y’ or ‘N’ characters,‘Y’ means will be visible and ‘N’ means won't be visible. The charactersare given in the order that the reactants are listed.

[0190] Stimulus: Any concept that has this attribute will be listed as astimulus in the Stimulus list in the Pathway wizard. Does not requireany particular value to be assigned.

[0191] Every substance or process is represented by a concept. Conceptscan be defined as special types of other concepts, and can contain otherconcepts. Concepts can be assigned attributes, and may assign values totheir attributes.

[0192] Concepts:

[0193] The formal specification for defining a concept is as follows:

[0194] CONCEPT <concept name> [EXPANDS <base concept>[;]] [CONTAINS<concept list>[;]] [EXCLUDES <concept list>[;]] [JOINS <conceptlist>[;]] [HAS <attribute list>[;]] [SETS <attribute assignment list>].

[0195] The grammar in square brackets [ ] is optional.

[0196] Some specific examples of definitions (with explanations):

[0197] Concept “object” has “mass”, “size”.

[0198] This statement defines a concept called “object” to which theattributes “mass” and “size” have been assigned.

[0199] Concept “protein” expands “object”.

[0200] This statement defines a concept called “protein” as a specifictype of “object”. The “protein” concept inherits the attributes of“object”, therefore it has attributes “mass” and “size” associated withit automatically.

[0201] Concept “TNFR” expands “protein”; has “abstract”; sets “mass”=30,“abstract”=“abstract of TNFR”.

[0202] This statement defines a concept called “INFR” as a specific typeof “protein”. It inherits the attributes of a “protein”, and thereforeautomatically has “mass” and “size” attributes. It gives itself an“abstract” attribute (documentation of the protein). It sets its “mass”attribute to 30 (for the time being, we will use normalized values forphysical attributes), and its “abstract” to the text “abstract of TNFR”.

[0203] Concept “generic cell” expands “object”; contains “nucleus”,“mitochondria”, “cell membrane”; excludes “RAF”; sets “size”=40.

[0204] This statement defines a concept called “generic cell” as aspecific type of “object”. It inherits “mass” and “size” attributes from“object”. It defines itself as a wrapper around the concepts “nucleus”,“mitochondria”, and “cell membrane”, and sets its “size” to 40. Itprevents the inheritance of the “RAF” concept from any of its childconcepts. Concepts that contain other concepts do not inherit attributesfrom the concepts they contain.

[0205] Concept “Active FADD” expands “protein”; joins “active”, FADD”.

[0206] This statement defines a concept called “Active FADD” as aspecific type of protein. It inherits the attributes of a protein, andjoins together the concepts “active” and “FADD”. Concepts that representconjoined concepts inherit attributes from the concepts they contain.Conjoined concepts currently have little utility in the presentinvention; activated proteins are represented as inheriting from theinactivated forms:

[0207] Concept “active FADD” expands “FADD”.

[0208] The events determine which concepts react, what concepts areproduced as a result, the processes that occur within the reaction, andwhat determines whether or not the reaction will proceed.

[0209] Events:

[0210] The formal specification for an event is as follows:

[0211] EVENT <event name> REQUIRES <concept list>[;] [TESTS <attribute>OF <concept> {EQUAL TO|LESS THAN|GREATER THAN} <attribute> OF<concept>[;]] [APPLIES <concept> FROM <concept>TO <concept>[;]][PRODUCES <concept list>[;]] [INHIBITED BY <concept list>[;]] [PRESENTIN <concept list>[;]] [ABSENT IN <concept list>[;]] [HAS <attributelist>[;]] [SETS <attribute assignment list>].

[0212] The grammar in square brackets [ ] is optional.

[0213] Some examples of definitions (with explanations):

[0214] Event “Three molecules of TNF binds to and trimerizes TNFR”

[0215] Requires “TNF”, “TNF”, TNF”, “TNFR”, “TNFR”, “TNFR”;

[0216] Applies “binds to” from “TNF” to “TNFR”;

[0217] Applies “trimerizes” from “TNF” to “TNFR”;

[0218] Produces “Trimer of TNFR”;

[0219] Has “duration”;

[0220] Sets “duration”=10.

[0221] This statement defines an event that requires three instances ofthe “TNFR” concept and three instances of the “TNF” concept to proceed.It produces the concept “Trimer of TNFR”, and requires a “duration” of10 to do so. It performs the reaction by applying the “binds to” and“trimerizes” concepts from “TNF” to “TNFR”. (The purpose of the‘applies’ clause is to break the reaction into pieces to describe theprocess to the static presentation engine.)

[0222] Event “GTP displaces GDP and activates heterotrimeric Gs protein”

[0223] Requires “GTP”, “GDP-bound heterotrimeric Gs protein”;

[0224] Tests “concentration” of “GTP” greater than “concentration” of“GDP”;

[0225] Produces “active heterotrimeric Gs protein”, “GDP”.

[0226] This statement defines an event that requires “GTP” and“GDP-bound heterotrimeric Gs protein” to proceed. It produces theconcepts “GDP” and “active heterotrimeric Gs protein”. It tests that theattribute “concentration” of concept “GTP” is numerically greater thanthe attribute “concentration” of concept “GDP”, and if so, permits thereaction to take place. No processes are specified, so if this eventoccurs it will not be fully animated. No duration is specified, so theanimation engine will assign it a default reaction time of 5 seconds.

[0227] Event “Adenylyl cyclase converts ATP to cAMP and Pi”

[0228] Requires “Adenylyl cyclase”, “ATP”;

[0229] Applies “converts ATP to” from “adenylyl cyclase” to “ATP”;

[0230] Present In “generic cell”;

[0231] Produces “cAMP”, “Pi”.

[0232] This statement defines an event that requires “adenylyl cyclase”and “ATP” to proceed. It produces the concepts “cAMP” and “Pi”. It willonly occur in a “generic cell” context. It performs the reaction byapplying the “converts ATP to” concept from “adenylyl cyclase” to “ATP”.(This may be an area of some contention as to which concept “performs”the action and which concept it is “performed on”. Naturally, the mostscientifically appropriate definition of the process should be used ifit is known.)

[0233] Event “TRADD binds to and activates TRAF2”

[0234] Requires “active TRADD”, “TRAF2”;

[0235] Inhibited by “FADD”;

[0236] Absent In “liver cell”;

[0237] Applies “binds to” from “TRADD” to “TRAF2”;

[0238] Applies “activates” from “TRADD” to “TRAF2”;

[0239] Produces “active TRAF2”.

[0240] This statement defines an event that requires “active TRADD” and“TRAF2” to proceed. It produces that concept “active TRAF2”. It performsthe reaction by applying “binds to” and “activates” from “TRADD” to“TRAF2”. The reaction will not occur if the concept “FADD” is present.The reaction will not occur in a liver cell (but will occur in everyother type of cell).

[0241] The following tables may be used by the system and method of thepresent invention. They are preferably stored in structure form inmemory. They are preferably read from and written to a structuredstorage document.

[0242] Data Tables:

[0243] The ANYVALUE structure is a VARIANT-like type that provides atransparent means of storing information of different types. Name TypeDescription Lnum long Part of an anonymous union, stores a long integervalue. Fnum double Part of an anonymous union, stores a double floatingpoint value. Index long Part of an anonymous union, stores an index intoa string table or enumerated value table. Error long Part of ananonymous union, stores an error code. Hasvalue bool Indicates whetherthe union contains a valid value. Type char Indicates the type of thedata contained within the union.

[0244] The ANATOMIC table holds the anatomical information. Name TypeDescription Anatomic_Id long Primary key for this table. Anatomicidentifier. Tissue long Identifies the tissue associated with theconcept. Reference_Id long Identifies the reference. CellType longIdentifies the cell type. MoleculesPerCell double Identifies themolecules per cell. CellLine text Identifies the cell lineDevelopmentalStage long Identifies the developmental stage. Organ longIdentifies the organ AnatExpression_Id long Identifies the anatomicalexpression.

[0245] The ANATOMICEXPRESSION table holds the types of anatomicalexpression information. Name Type Description AnatExpression_ID longPrimary key for this table. Anatomic identifier. Tissue text Identifiesthe anatomical expression type (e.g. Protein, RNA, etc.)

[0246] The APPLIES table holds the applies process information. NameType Description Apply_Id long Primary key for this table. Identifierfor the table. Apply_Concept long Identifies the concept that isapplied. From_Concept long Identifies the concept that the relationshipcomes from. To_Concept long Identifies the concept the relationshippoints to.

[0247] The ASSAYNAME table holds the names of the assays used in thegeneration of the events. Name Type Description Assay_Id long Primarykey for this table. Applies identifier. Name Text Identifies the name ofthe assay.

[0248] The ATTRIBUTEENUMVALUE table holds all possible enumerated valuesfor all enumerated list attributes. The offset within this tableidentifies which element of the enumerated list an enumerated listattribute represents. Name Type Description AttributeENum_Id longComposite key for this table with Name. Attribute type identifier. Nametext Composite key for this table with AttributeENum_Id. Name of theattribute (e.g. shape, cellular location, etc.)

[0249] The ATTRIBUTES table holds the attribute definitions. Name TypeDescription Attribute_Id long Primary key for this table. Attributeidentifier. Name text Name of the attribute. Type long Identifies thetype of the attribute. (e.g. integer, real, enumerated list, etc.)Bounds char Identifies the boundary limits of the attribute, if it is anumber. Upperbound long Stores the upper bound of the attribute if it isnumerical. Lowerbound long Stores the lower bound of the attribute if itis numerical. Upperexact long Indicates whether the upper bound isinclusive if the attribute is numerical. Lowerexact long Indicateswhether the lower bound is inclusive if the attribute is numerical.

[0250] The AUTHORLINK table holds the links between authors andreferences. Name Type Description AuthorLink_Id long Primary key forthis table. Author link identifier. Author_Id long Identifies theauthor. Reference_Id long Identifies the reference.

[0251] The AUTHORS table holds the author information. Name TypeDescription Author_Id long Primary key for this table. Authoridentifier. Name Text Identifies the name of the author.

[0252] The CLASSES table holds the hierarchical relationships betweenconcepts. Name Type Description Concept_Id long Primary key for thistable. Concept identifier. Parent long Parent of the concept.ClassType_Id long Class type identifier.

[0253] The CLASSTYPE table holds the hierarchical relationship types.Name Type Description ClassType_Id long Primary key for this table.Class type identifier. Description long Describes the class type.

[0254] The COMMENT table holds the comment information provided by theeditors. Name Type Description Comment_Id long Primary key for thistable. Comment identifier. CommentType_Id long Identifies the type ofcomment. (e.g. editor comments, scope notes, user notes, etc . . . )CommentRefType_Id long Identifies the comment reference type as“concept” or “event”. Id long Identifies the concept or event Id that isassociated with the given comment. Comment text Editor comments.

[0255] The COMMENTREFTYPE table holds the comment reference typeinformation. Name Type Description CommentRefType_Id long Primary keyfor this table. Comment reference type identifier. Name text Name of thecomment reference type. (Concept or Event)

[0256] The COMMENTTYPE table holds the comment type information. NameType Description CommentType_Id long Primary key for this table. Commentreference type identifier. (e.g. editor comments, scope notes, usernotes, etc . . . ) Name text Name of the comment type.

[0257] The COMPAREENUM table holds the enumerated list values forattribute comparison. Name Type Description Compare_Id Long Primary keyfor this table. Comparison identifier. (e.g. equal to, less than, notgreater than, etc . . . ) Name Text Name of the comparison type.

[0258] The CONCEPTATTRIBUTE table holds the concept attributeinformation. Name Type Description Concept_Id long Composite key forthis table with Attribute_Id. Concept identifier. Attribute_Id longComposite key for this table with Concept_Id. Attribute identifier.StoredValue text Identifies the value of the concept's attribute.HasValue bool Concept attribute indicator. Type long Identifies theattribute type.

[0259] The CONCEPTS table holds the concept definitions. Name TypeDescription Concept_Id long Composite key for this table. Conceptidentifier. User_Id long Composite key for this table. User identifier.Expands long Indicates another concept that the concept is based on.Version_Id long Indicates the version of the concept for documentationpurposes. Organism long Indicates the organism the concept was presentin. Transportable bool Indicates whether the concept has thetransportable feature. Homolog_Of long Indicates what homolog(s) theconcept may have. GeneProteinFamily long Indicates concept membership ina gene or protein family. Homolog_Flag long Indicates whether theconcept is a homolog of another concept.

[0260] The DBUI table holds the reference information for outsidedatabases and unique identifiers. Name Type Description DBUI_Id longPrimary key for this table. DBUI identifier. DBUIType long Identifiesthe type of DBUI. DB long Identifies the database type UI textIdentifies the UI type.

[0261] The DBUITYPE table holds the enumerated type values for the DBUI.Name Type Description DBUIType_Id Long Primary key for this table. DBUItype identifier. Name Text Name of the DBUI type. (e.g. string, numeric)

[0262] The EVENTATTRIBUTE table holds the relationships between theevents and the event attributes. Name Type Description Event_Id longComposite key for this table with Apply_Id. Event identifier.Attribute_Id long Composite key for this table with Event_Id. Attributeidentifier. StoredValue text Actual value of the event attribute.HasValue bool Event attribute indicator. Type long Identifies attributetype.

[0263] The EVENTS table holds the event definitions. Name TypeDescription Event_Id long Composite key for this table. Eventidentifier. User_Id Long Composite key for this table. User identifier.Controversy long Name or description of the event. CellularLocation longIndicates whether this event has one or more Applies clauses (thatdefine the processes in the event). Version_Id long Indicates whetherthis event has one or more Tests clauses. TransportLocation longIndicates whether this event has one or more attributes.EguilibriumConstantEQ long Equilibrium constant. DissociationConstantKDlong Dissociation constant. ForwardKineticRateConstantK1 long Forwardkinetic rate constant. ReverseKineticRateConstantK1 long Reverse kineticrate constant. MichaelKM long Michaelis-Menten constant EnzymaticVMaxlong Enzymatic maximum velocity. KineticDis la bool Kinetic displayindicator. CompletedConstants bool Completed constant indicator.

[0264] The EVENTSPECIES table holds the event identifiers and thereference identifiers. Name Type Description Event_Id long Primary keyfor tbis table. Event identifier. Organism long Organism identifier.

[0265] The EXPCONDITIONS table holds the experimental conditions inwhich the event was described. Name Type Description ExpCondition_Idlong Primary key for this table. Experimental condition identifier.Reference_Id long Identifier for references. Assay long Identifier forassay. Preparation_Type long Identifier for preparation type.AssayProcess text Assay process description. AssayBuffer text Assaybuffer description. TemperatureC long Temperature in degrees celcius.

[0266] The EXTERNALDB table holds the DB identifier and the associateddatabase name. Name Type Description DB_Id long Primary key for thistable. Database identifier. Name long Name of the database.

[0267] The GENCONCEPT table holds the generic concept details. Name TypeDescription GenConcept_Id long Primary key for this table. Genericconcept identifier. GenConcept long Identifier for generic concepts.Concept_Id long Identifier for concepts. Type_Id long Identifier fortype. Value text Generic concept value

[0268] The GENCONCEPTTYPES table holds the generic concept types. NameType Description Type_Id long Primary key for this table. Genericconcept type identifier. Name text Name of the generic concept types(e.g inhibitors, activators, motifs, domains, modifications etc.)

[0269] The JOURNAL_SOURCE_REF table holds the journal sourceinformation. Name Type Description Journal_Id long Primary key for thistable. Journal identifier. Name Text Name of the journal. Tier LongJournal quality tier as classified by New World. (e.g. Tier One, TierTwo, etc.)

[0270] The MODIFIESATTRIBUTE table holds the attribute modificationinformation. Name Type Description Modification_Id long Primary key forthis table. Attribute modification identifier. Concept_Id longIdentifier for concepts. Operator_Id long Identifier for operator.Attribute_Id long Identifier for attribute. StoredValue text Value ofattribute modification. Type text Attribute type

[0271] The NAMES table holds the name information. Name Type DescriptionName_Id long Primary key for this table. Name identifier. Name textValue of the name. Type_Id long Name type

[0272] The NAMETYPE table holds the name type definitions. Name TypeDescription Type_Id long Primary key for this table. Name typeidentifier. Name text Value of the name type (e.g. preferred name,synonym, official name, etc.)

[0273] The OPERATOR table holds the operator definitions. Name TypeDescription Operator_Id long Primary key for this table. Operatoridentifier. Name text Value of the operator name (e.g. multiply, set,increment, etc.)

[0274] The PACKAGES table holds the client package information. NameType Description Package_Id long Primary key for this table. Packageidentifier. User_Id long Identifier for the user. Name text Packagename. Description text Package description

[0275] The PREPARATIONNAME table holds the information preparations.Name Type Description Preparation_Id long Primary key for this table.Preparation identifier. Name text The name of the preparation.

[0276] The REACTIONS table holds the reaction relationship information.Name Type Description Reaction_Id long Primary key for this table.Reaction identifier. Event_Id long Identifier for events. Concept_Idlong Identifier for concepts. Type_d long Identifier for reaction type.Stoichiometry_Data long Reaction stoichiometry.

[0277] The REACTIONTYPE table holds the reaction types. Name TypeDescription Type_Id long Primary key for this table. Reactionidentifier. Name text The name of the reaction. (e.g. requires,inhibited by, produces, excluded from, present in, etc.)

[0278] The REAGENTS table holds the event reagent information. Name TypeDescription Concept_Id long Primary key for this table. Conceptidentifier. Reference_Id long Identifier for references. Name longReagent name.

[0279] The REFERENCE table holds the reference information. Name TypeDescription Reference_Id long Primary key for this table. Reactionidentifier. Journal long Identifier for journal. Tide text Referencetitle. Year long Reference year. Volume text Referene volume. Issue textReference issue. Page_Start text Reference start page. Page_End textReference end page. PMID long Reference PMID. Review bool Referencereview indicator.

[0280] The RELATIONSHIPTYPE table holds the relationship typedefinitions. Name Type Description Type_Id long Primary key for thistable. Relationship type identifier. Name long Relationship type name.

[0281] The SECURITY table holds the concept and event securityrelationships. Name Type Description Type long Composite key for thistable with Event_Id and Concept_Id. Security type. Event_Id longComposite key for this table with Type and Concept_Id. Event identifier.Concept_Id long Composite key for this table with Type and Event_Id.Concept identifier. Package_Id long Security package identifier.

[0282] The TESTSATTRIBUTE table holds the attribute information for thetests functionality. Name Type Description Test_Id long Primary key forthis table. Test identifier. Concept1 long First concept identifier forthe test functionality. Compare long Comparison identifier. Attribute1long First attribute identifier for the test functionality. Attribute2long Second attribute identifier for the test functionality. Concept2long Second concept identifier for the test functionality.

[0283] The TIER table holds the reference tier definitions. Name TypeDescription Tier_Id long Primary key for this table. Tier identifier.Description text The description of the tier. (e.g. Tier One, Tier Two,etc.)

[0284] The USERS table holds the user security information information.Name Type Description User_Id long Primary key for this table. Useridentifier. Password text User password. Login text Login informationfor the user. Full_Name text User full name.

[0285] The VERSION table holds the user edit trail for data edited inthe database. Name Type Description Version_Id long Primary key for thistable. User identifier. Name text User password. VersionDate text Logininformation for the user. ActionType text Edit action type. (e.g.Creation, Editing Deletion, etc.)

[0286] The VERSIONJUNCTION table holds the version information forconcepts and events. Name Type Description Version_Id long Primary keyfor this table. Version identifier. Concept_Id long Concept identifier.Event_Id long Event identifier.

[0287] In another embodiment of the present invention, theaforementioned information may be enhanced to model the threedimensional conformation of identified regions (in a protein understudy) that might mediate protein-protein interactions. In a furtherembodiment of the present invention, reference links at key programsites provide the User 20 rapid access to more detailed publishedinformation. Hyperlinks are also provided at suitable locations pointingto organism-specific databases.

[0288] In another embodiment of the present invention, a User 20 mayexamine more closely the molecular details of any component in theproposed pathway. This ability has the advantage of allowing the User 20to effectively zoom in and out on any pathway element for a closer(molecular) or broader (sub-cellular or cellular) look. For example, a aUser 20 may take a closer look at the three dimensional conformation ofa binding site and its interaction with the target site. The effect ofsequence alterations or covalent modification of binding site subunits(e.g., by phosphorylation) may also be examined more closely. Thisinformation is advantageous in drug design studies, prediction oftoxicity and side effects, and susceptibility issues due to geneticvariation among diverse populations.

[0289] Although the present invention has been described in terms ofparticularly preferred embodiments, it is not limited to theseembodiments. Alternative embodiments and modifications which would stillbe encompassed by the invention may be made by those skilled in the art,particularly in light of the foregoing teachings. For example, althoughthe present invention has been described in connection with thesimulation of biochemical pathways, it could be used for otherapplications. For example, the Inference Engine 14 of the SimulationModule 10 may be adapted to process-information to predict automotive orcomputer network traffic. For this type of application, the Database 80may contain known traffic concepts (e.g., cars, trucks, different typesof weather, accidents, etc.) and known traffic events. These conceptsand events may then be processed by the Inference Engine 14 of theSimulation Module 10 to predict traffic effects given a trafficstimulus.

[0290] Accordingly, this invention is intended to cover any alternativeembodiments, modifications or equivalents which may be within the spiritand scope of the invention.

We claim:
 1. A system for demonstrating signal cascades that occur incertain cells when certain stimuli are introduced, comprising: (a) adatabase of known cellular components and reactions; and (b) aninference engine for generating signal cascades, wherein the inferenceengine is linked to the database.
 2. The system of claim 1, wherein thedatabase comprises concepts, events and attributes.
 3. The system ofclaim 2, wherein said concepts are adapted to inherit from otherconcepts.
 4. The system of claim 2, wherein said concepts contain otherconcepts.
 5. The system of claim 2, wherein said concepts exclude otherconcepts.
 6. The system of claim 2, wherein said concepts are capable ofjoining other concepts.
 7. The system of claim 2, wherein said conceptsare associated with said attributes.
 8. The system of claim 2, whereinsaid attributes comprise indicia of shape, color, location of a graphic,time, or species.
 9. The system of claim 2, wherein said databasecomprises signal transduction information.
 10. The system of claim 2,wherein said database comprises pathology information.
 11. The system ofclaim 2,, wherein said database comprises information specific tochemical areas.
 12. The system of 11, wherein said information comprisessignal transduction information on plant cellular environments or animalcellular environments.
 13. The system of claim 1, wherein the databasecomprises data for binding constants, rate equations, reactantconcentrations, primary sequences of functional sites in biomolecules orproteins, or efficacy of physical interactions with binding partners.14. A computer-implemented method for a reverse pathway comprising: (a)providing information regarding a target cellular environment and anendpoint; (b) simulating at least one aspect of a reverse pathway basedon the information provided regarding the target cellular environmentand the endpoint; and (c) displaying at least one aspect of the reversepathway.
 15. A computer-implemented method of predicting pathwayscomprising: (a) simulating signal cascades of pathways that occur whenstimuli are introduced; (b) dynamically generating results using asimulation module, the simulation module comprising an inference enginelinked to at least one dynamic database, the at least one dynamicdatabase containing definitions relating to cellular concepts,components and reactions.
 16. A computer-implemented method forsimulating at least one aspect of a cellular biochemical pathwaycomprising: (a) providing information regarding a target cellularenvironment and a stimulus event; (b) simulating at least one aspect ofa cellular biochemical pathway based on the information providedregarding the target cellular environment and the stimulus event; and(c) displaying at least one aspect of the cellular biochemical pathway.17. The method of claim 16, wherein the step of displaying furthercomprises textually or graphically displaying at least one aspect of thecellular biochemical pathway.
 18. The method of claim 16, wherein themethod further comprises predicting target biological outcomes.
 19. Themethod of claim 16, wherein the method further comprises predictingpotential target protein interaction partners.
 20. A system forsimulating at least one aspect of a cellular biochemical pathwaycomprising: (a) a data input interface for receiving cellularenvironment information and stimuli information; (b) a simulation modulethat generates at least one simulated pathway for at least one aspect ofa cellular pathway by determining an order of cellular events that occurwithin a defined cellular environment, wherein the simulation is basedon the cellular environment and stimuli information received by the datainput interface; and (c) a display module that displays a representationof the at least one simulated pathway.
 21. The system of claim 20,wherein the representation comprises a textual representation.
 22. Thesystem of claim 20, wherein the representation comprises a graphicalrepresentation.
 23. The system of claim 20, further comprising aprediction module.
 24. The system of claim 23, wherein the predictionmodule predicts at least one biological outcome based on the at leastone simulated pathway.
 25. The system of claim 24, wherein the at leastone biological outcome comprises apoptosis or lymphocyte activation. 26.The system of claim 23, wherein the prediction module predicts at leastone protein interaction partner based upon the at least one simulatedpathway.
 27. The system of claim 23, wherein the prediction modulepredicts at least one gene interaction site based upon the at least onesimulated pathway.
 28. The system of claim 27, wherein the at least onegene interaction site is for transcription factors.
 29. A method forgenerating a representation of a biochemical pathway, comprising:providing as inputs: (a) a set of separately defined concepts andevents, (b) a physiological context of the biochemcial pathway, (c) atleast one stimulus, and (d) an event corresponding to the at least onestimulus; and dynamically determining substances available to thebiochemical pathway and an order in which events occur in thebiochemical pathway.
 30. The method of claim 29, wherein the separatelydefined concepts may be associated with various attributes.
 31. Themethod of claim 30, wherein the various attributes comprise informationon shape, color, size or location of a graphic.
 32. The method of claim29, wherein at least one of the defined concepts comprises a contextualstructure.
 33. The method of claim 29, wherein at least one of thedefined concepts is a compartment within a cell, part or all of anorganelle, a cellular membrane, a cytoskeletal structure, a cell, anextracellular fluid, an extracellular structure, a tissue, an organ, ora compartment within an organ.
 34. The method of claim 29, wherein atleast one of the defined events may be associated with at least oneattribute.
 35. The method of claim 34, wherein the at least oneattribute comprises reactants, products, inhibitors, and a contextwithin which the at least one of the defined events may occur.
 36. Themethod of claim 34, wherein the at least one attribute comprisesinformation that the at least one of the defined events is inhibited byat least one inhibitor or is inhibited from occurring in at least onelocation.
 37. The method of claim 29, wherein the biochemical pathwaycomprises a signal transduction pathway.
 38. The method of claim 29,wherein the biochemical pathway effects catabolism, anabolism,regulation of oxidative metabolism, regulation of transcription,regulation of protein synthesis, regulation of cell differentiation, orregulation of cell division.
 39. The method of claim 29, wherein thebiochemical pathway is characteristic of a disease.
 40. The method ofclaim 29, further comprising displaying a representation of at leastpart of the biochemical pathway.
 41. The method of claim 40, wherein therepresentation comprises a textual description of objects and processesof at least part of the biochemical pathway, listed in an order in whichthe objects and processes occur in the pathway.
 42. The method of claim40, wherein the representation comprises a textual description ofobjects and processes of at least part of the biochemical pathway,listed in an order in which the objects and processes occur in order oftime step.
 43. The method of claim 40, wherein the representationcomprises a graphical representation of objects and processes of atleast part of the biochemical pathway, wherein at least one of theobjects is represented by a graphic symbol having a combination ofcolor, shape, and size unique for the at least one object.
 44. Themethod of claim 43, further comprising displaying at least one textuallabel that identifies the at least one object that is represented by thegraphic symbol.
 45. The method of claim 43, further comprisingdisplaying at least one textual label that identifies at least one ofthe processes.
 46. The method of claim 43, further comprising displayinga static graphical representation of part or all the biochemicalpathway.
 47. The method of claim 43, further comprising displaying adynamic animated graphical representation of part or all of thebiochemical pathway.
 48. A method for generating a representation of anevent of a biochemical pathway comprising, providing as inputs: (a) aset of separately defined reactants of the event, (b) a physiologicalcontext of the event, and (c) at least one defined substance that is astimulus of the event; and dynamically determining an event of thebiochemical pathway, comprising a process that is an immediate result ofthe stimulus.
 49. The method of claim 48, wherein the process that is animmediate result of the stimulus is a reaction in which at least onereactant of the biochemical pathway reacts and from which at least oneproduct or process of the biochemical pathway is produced.
 50. Themethod of claim 48, wherein the event of the biochemical pathway isdynamically determined with an inference engine.
 51. A method ofdetermining an effect that modulating one or more reactions in abiochemical pathway has on an operation of the biochemical pathway,comprising: (a) generating and displaying a representation of a firstbiochemical pathway by dynamically determining substances and processesthat form the first biochemical pathway, and an order in which thesubstances appear and the processes occur in the first biochemicalpathway; (b) generating and displaying a representation of a secondbiochemical pathway, wherein a definition of at least one substance orprocess of the first biochemical pathway is changed so as to modulate atleast one reaction of the first biochemical pathway; and (c) comparingthe representations of the first and second biochemical pathways anddetermining an effect of modulating the at least one reaction of thefirst biochemical pathway.
 52. A method of identifying a potentialpharmacological target in a biochemical pathway that affects aphysiological condition of an organism, comprising: (a) generating anddisplaying a representation of a first biochemical pathway bydynamically determining substances and processes that form the firstbiochemical pathway, and an order in which the substances appear and theprocesses occur in the first biochemical pathway; (b) generating anddisplaying a representation of a second biochemical pathway wherein adefinition of at least one substance or process of the first biochemicalpathway is changed so as to modulate at least one reaction of the firstbiochemical pathway; and (c) comparing the representations of the firstand second biochemical pathways and determining an effect of modulatingthe at least one reaction of the first biochemical pathway; wherein asubstance of the first biochemical pathway is a potential target for adrug that modulates the reactivity when the substance participates in areaction which, when modulated, alters the biochemical pathway in adesired manner.
 53. A device for generating a representation of abiochemical pathway, comprising: (a) means for entering data; (b) anelectronic storage media that stores definitions of substances andprocesses of the biochemical pathway; (c) a data processing unit thatgenerates a representation of the biochemical pathway; and (d) means fordisplaying a representation of at least one substance or process of thebiochemical pathway; wherein the definitions of each substance andprocess comprises at least one attribute of the substance or process.54. A device for generating a representation of a biochemical pathwayevent, comprising: (a) a device for entering input data; (b) anelectronic storage media that stores definitions of substances andprocesses from which the biochemical pathway is formed; (c) a dataprocessing unit that, in response to inputs comprising at least onedefined substance or process that is a stimulus of the biochemicalpathway event, dynamically determines the biochemical pathway event bydetermining a process that is an immediate result of the stimulussubstance or process; and (d) a display device that displays arepresentation of at least one substance or process of the biochemicalpathway; wherein the definitions of each substance and process comprisesat least one attribute of the substance or process.
 55. The device ofclaim 54, wherein the process that is an immediate result of thestimulus is a reaction in which at least one substance of thebiochemical pathway reacts and from which at least one product orprocess of the biochemical pathway is produced.
 56. A device forgenerating a representation of a pathway, comprising: (a) means forentering data; (b) means for storing definitions of concepts and eventsof the pathway; (c) means for generating a representation of thepathway; and (d) means for displaying a representation of at least oneconcept or event of the pathway; wherein the definitions of each conceptand event comprises at least one attribute of the concept or event.